Elucidating SARS-CoV-2 Neurotropism: A Comprehensive Mendelian Randomization Study on Cerebrospinal Fluid Biomarkers and their Relevance to COVID-19 Neurological Manifestations

A mendelian randomization (MR) analysis was conducted to investigate whether SARS-CoV-2 invaded the human nervous system. This was confirmed by an increase in biomarkers found in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients. To confirm the neuroinvasive properties of SARS-CoV-2, a series of analyses were conducted utilizing accessible datasets by MR. In addition, external validation was conducted by testing specific proteins in a retrospective cohort study, which included 40 COVID-19 patients with neurological complications and 15 disease controls (DC). Our investigation revealed the hospitalization, severity of COVID-19 increased the area and volume of certain brain regions, but no other significant causal effects were found of brain imaging-derived phenotypes (IDPs) on COVID-19. Notably, the COVID-19 hospitalization significantly increased the area and volume of the left caudal middle frontal gyrus (p_fdr = 0.012; p_fdr = 0.012, respectively). Additionally, COVID-19 severity was linked to the area, volume of the right caudal anterior-cingulate cortex and the volume of the right cuneus cortex (p_fdr = 0.023; p_fdr = 0.025; p_fdr = 0.026, respectively). In the CSF of COVID-19 patients, the median level of CHI3L1 was significantly higher (13677 pg/mL) compared to the DC group (8421 pg/mL, p < 1.00E-04). Similar trends were also found in CSF KLK6 and NGF-β. Additionally, the median NRGN level in plasma was significantly higher in the COVID-19 group (1013.00 pg/mL) compared to the control group (360.00 pg/mL, p = 6.50E-03). A subgroup analysis demonstrated that COVID-19 patients experiencing moderate to critical symptoms exhibited higher levels of GFAP in their CSF compared to those without. Elevated CSF levels of GFAP and S100B were also found in COVID-19 patients with decreased consciousness and comorbidities. This MR analysis provided evidence that SARS-CoV-2 may invade the human nervous system, as indicated by the increased levels of CSF biomarkers CHI3L1, NGF-β, and KLK6 in COVID-19 patients. These findings suggested that neuroinflammation could be a potential mechanism underlying the neurological complications seen in COVID-19 patients.