Central nervous system and systemic inflammation networks associated with acute neurological outcomes in COVID-19

COVID-19 patients show neurological manifestations, and distinct mechanisms have been proposed. Here, we show functional protein network analysis with cytokines, growth factors, and neuroinflammation biomarkers altered in cerebrospinal fluid (CSF) and sera from COVID-19 patients with isolated headache (n=12), encephalopathy (n=22), and inflammatory neurological diseases (IND) (n=14) compared to uninfected controls (n=9). The CSF of COVID-19 patients had enriched factors for STAT signaling (GO:0042531 and GO:0007259), Th2 response (GO:0002830), and Adverse outcome in COVID-19 (WP4891). Headache and encephalopathy were also associated with Monocyte chemotaxis (GO:0002548) and NK cell activity (GO:0030101 and GO:2000503). Encephalopathy was also associated with Neuroinflammation (GO:0150077 and GO:0150078), Tissue remodeling (GO:0034105), Microglial functions (GO:1903978 and GO:1904141), VEGF production (GO:0010573), EGF signaling (GO:0038134), Th1 cytokines (GO:2000556), Regulation of cell adhesion molecules (GO:0060353), Neuron  homeostasis (GO:0070050), ILC development and heterogeneity (WP3893), while IND was related to DC activation (GO:0001773), Leukocyte adhesion (GO:1904996), Th1 (GO:0042088) and Th2 (GO:0002830) responses, T cell proliferation (GO:0042104), and Glial cell proliferation (GO:0060252). Serum analysis showed unrelated processes in IND, but patients with headache and encephalopathy had processes favoring Tissue fibrosis (WP5095), Neuroinflammation and glutamatergic signaling (WP5083), and Mitochondrial oxidative stress and endothelial dysfunction (WP5183). Encephalopathy was also associated with VEGF production (GO:0010573), Th2 response (GO:0002830), Leukocyte adhesion (GO:1904996), and Prostaglandin signaling (WP5088). These results suggest that cytokine storm-driven events are associated with glial activation, blood-brain barrier and vascular disturbs and development of encephalopathy and IND.