PT  - JOURNAL ARTICLE
AU  - Estibaliz Santiago-Mujika
AU  - Kevin Heinrich
AU  - Sonia George
AU  - Colt D Capan
AU  - Cameron Forton
AU  - Zachary Madaj
AU  - Amanda R Burmeister
AU  - Matthew Sims
AU  - J Andrew Pospisilik
AU  - Patrik Brundin
AU  - Stewart F Graham
AU  - Lena Brundin
TI  - Increased levels of circulating neurotoxic metabolites in patients with mild Covid19
AID  - 10.1101/2022.06.22.497189
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.22.497189
4099  - http://biorxiv.org/content/early/2022/06/24/2022.06.22.497189.short
4100  - http://biorxiv.org/content/early/2022/06/24/2022.06.22.497189.full
AB  - SARS-CoV-2 corona virus causes a multi-faceted and poorly defined clinical and pathological phenotype involving hyperinflammation, cytokine release, and long-term cognitive deficits, with an undefined neuropathological mechanism. Inflammation increases the activity of the kynurenine pathway, which is linked to neurodegenerative and psychiatric disorders. We sought to determine whether the kynurenine pathway is impacted in patients with mild COVID-19, leading to elevated neurotoxic metabolites in blood, and whether such changes are associated with pro-inflammatory cytokines. Serum samples were taken from 150 patients and analyzed by ELISA and ultra-high performance liquid chromatography (UHPLC). The data were analyzed using multiple linear regression models adjusted for age and sex. We found increased levels of kynurenine, quinolinic acid and 3-hydroxykynurenine in serum from patients with mild COVID-19, together with increased levels of IL-6, ICAM-1, VCAM-1 and neopterin. The levels of neurotoxic metabolites were significantly associated with key inflammatory cytokines including IL-6 and TNFα. The COVID-19 risk-factor hypertension was associated with the highest levels of neurotoxic metabolites in plasma. These neuroactive metabolites could be part of the pathological mechanisms underlying cognitive impairment during and post-COVID and should be explored as potential biomarkers for long-COVID symptoms.Competing Interest StatementP.B. has received support as a consultant from Calico Life Sciences, CureSen, Enterin Inc, Idorsia Pharmaceuticals, Lundbeck A/S, AbbVie, Fujifilm-Cellular Dynamics International, and Axial Therapeutics. He has received commercial support for research from Lundbeck A/S and F. Hoffman-La Roche. He has ownership interests in Acousort AB, Axial Therapeutics, Enterin Inc and RYNE Biotechnology. During the time that this paper was written he became an employee of F. Hoffman-La Roche, although none of the data were generated by this company.3-HK3-HydroxyKynurenineAAAnthranilic AcidBBBBlood Brain BarrierCOVID-19Coronavirus Disease (2019)CIConfidence IntervalCSFCerebrospinal FluidGluGlutamateICAM-1Intercellular Adhesion Molecule 1ICUIntensive Care UnitIDOIndoleamine 2,3-DioxygenaseIFN-ɣInterferon GammaILInterleukinsKYNKynurenineKYNAKynurenic AcidPAPicolinic AcidPCRPolymerase Chain ReactionROSReactive Oxygen SpeciesS100BS100-Calcium-Binding Protein BSAASerum Amyloid ASARS-CoV-2Severe Acute Respiratory Syndrome Coronavirus 2SIVSimian Immunodeficient VirusTNF-αTumor Necrosis AlphaTRPTryptophanQUINQuinolinic acid