Increased galanin-galanin receptor 1 signaling, inflammation, and insulin resistance are associated with affective symptoms and chronic fatigue syndrome due to Long COVID

Abstract Background Long COVID (LC) patients frequently suffer from neuropsychiatric symptoms, including depression, anxiety, and chronic fatigue syndrome (CFS), relabeled as the physio-affective phenome of LC. Activated immune-inflammatory pathways and insulin resistance key play a role in these physio-affective symptoms due to LC. Aims To examine the associations between the Hamilton Depression (HAMD), Hamilton Anxiety (HAMA) and Fibro-Fatigue (FF) Rating Scale scores and serum C-reactive protein (CRP), prostaglandin E2 (PGE2), galanin-galanin receptor 1 (GAL-GALR1) signaling, insulin resistance, insulin-like growth factor (IGF-1), plasminogen activator inhibitor-1 (PAI1), and damage biomarkers such as S100B and neuron-specific enolase (NSE) in 90 subjects 3-6 months after acute SARS-CoV-2 infection. Results LC patients show higher HAMD, HAMA, and FF scores, CRP, PGE2, GAL-GALR1 signaling, insulin resistance, PAI1, NSE, and S100B than participants without LC. The HAMD/HAMA/FF scores were significantly correlated with PGE, CRP, GAL, GALR1, insulin resistance, and PAI1 levels, and a composite score based on peak body temperature (PBT) – oxygen saturation (SpO2) (PBT/SpO2 index) during the acute infectious phase. A large part of the variance in the affective and CFS symptoms (33.6%-42.0%) was explained by a combination of biomarkers; the top-3 most important biomarkers were GAL-GALR1 signaling, PGE2, and CRP. Inclusion of the PBT/SpO2 index increased the prediction considerably (55.3%-67.1%). The PBT/SpO2 index predicted the increases in GAL-GALR1 signaling. Conclusions These findings suggest that the affective symptoms and CFS of Long COVID are largely the consequence of activated immune-inflammatory pathways, metabolic aberrations, and the severity of the inflammation during acute SARS-CoV-2 infection.