Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19
Nicole Lardini Freitas, João Victor Carvalho Deus, Karen Sampaio, Yago Côrtes Pinheiro Gomes, Rafael Carvalho Torres, Carlos Otávio Brandão, Cristiane Nascimento Soares, Marcus Tulius Teixeira Silva, Otávio Melo Espíndola
Scientific Reports, doi:10.1038/s41598-025-08632-9
COVID-19 is associated with a wide spectrum of neurological alterations, ranging from headache and dizziness to severe encephalopathy and inflammatory neurological diseases (IND), and neuropathological findings suggest immune-mediated processes. Therefore, we sought to characterize profiles of cytokines, chemokines, growth factors, and markers of central nervous system (CNS) homeostasis in COVID-19 patients with neurological alterations to identify key factors and mechanisms underlying CNS disturbances in COVID-19. The study included a case series of 52 COVID-19 patients with neurological manifestations, which were categorized into three groups: isolated refractory headache (n = 14), encephalopathy (n = 24), and IND (n = 14). Individuals with non-inflammatory, noninfectious neurological conditions (n = 9) were included as negative controls. Paired CSF and serum samples were assessed for 56 biomarkers. Regardless of the neurological condition, COVID-19 patients exhibited elevated CSF levels of proinflammatory mediators, including IL-2, IL-3, IL-6, IL-15, IL-25, IFN-α2, CCL7, CCL11, and GM-CSF. Patients with encephalopathy and IND also showed increased IL-1β, IL-18, TNF-α, neopterin, IL-7, CXCL8, CXCL9, TGF-α, EGF, sTREM-2, and HMGB1, consistent with a CNS cytokine storm. In contrast, individuals with isolated refractory headache showed a modest inflammatory profile, compatible with the limited CNS involvement. COVID-19 patients showed elevated serum IL-13, IL-18, TNF-α, VILIP-1, TGF-α, and VEGF levels, indicating systemic inflammation and potential blood-brain barrier (BBB) disruption. β-NGF was increased in the CSF of patients with encephalopathy and IND, suggesting the activation of neuroprotective responses during patient recovery. Functional protein network analysis showed a significant enrichment of interactions between factors altered in the CSF of patients with encephalopathy and IND, many of them related to processes of neuroinflammation and microglial functions, and leukocyte chemotaxis, activation and proliferation. These findings support a model in which both systemic immune activation and localized neuroinflammation contribute to the diversity of neurological outcomes observed in COVID-19, and dysregulated cytokine production, glial activation, inflammasome activity and BBB disturbances represent key factors in neuro-COVID-19 pathogenesis. At the onset of the Coronavirus Disease 2019 (COVID-19) pandemic, many groups reported the involvement of the central and peripheral nervous systems in SARS-CoV-2 infection. Patients displayed neurological manifestations as the initial presentation or after the onset of classic symptoms such as fever, cough, diarrhea, and fatigue 1-6 . Central nervous system (CNS) manifestations, including headache, dizziness, altered consciousness, and acute cerebrovascular disease, were more common in severe cases than in patients with mild to moderate symptoms as determined by their respiratory status 5 . In..
Author contributions N.L.F. performed cytometry bead-based multiplex assays with assistance from R.C.T., conducted ELISA, data analysis, and drafted the manuscript; J.V.C.D. carried out functional network analysis; K.S., performed Luminex assays; Y.C.P.G. performed data analysis; C.O.B. performed CSF and paired serum laboratory analysis; C.N.S. and M.T.T.S. acquired clinical data and conducted neurological assessments; N.F.L., J.V.C.D., and O.M.E assembled the figures; O.M.E. and M.T.T.S contributed to the study concept and design; O.M.E performed data analysis, supervised all phases of the project, and drafted the manuscript. All authors contributed to interpretation of the results, read and approved the final manuscript.
Declarations
Competing interests The authors declare no competing interests.
Ethics approval and consent to participate The study protocol was approved by the Brazilian National Committee of Ethics in Research on April 22, 2020 (Protocol number CAAE 30611720.6.0000.5262), and written informed consent was obtained from all participants. All methods were performed in accordance with the relevant guidelines and regulations.
Additional information
Supplementary Information The online version contains supplementary material available at h t t p s : / / d o i . o r g / 1 0 . 1 0 3 8 / s 4 1 5 9 8 -0 2 5 -0 8 6 3 2 -9 . Correspondence and requests for materials should be addressed to O.M.E. Reprints and permissions information is available at ..
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