Citation: Zingaropoli, M.A.; Pasculli, P.; Barbato, C.; Petrella, C.; Fiore, M.; Dominelli, F.; Latronico, T.; Ciccone, F.; Antonacci, M.; Liuzzi, G.M.; et al. Biomarkers of Neurological Damage: From Acute Stage to Post-Acute Sequelae of COVID-19. Cells 2023, 12, 2270. https://doi.org/10.3390/ cells12182270 Academic Editor: Alexander E. Kalyuzhny Received: 27 July 2023 Revised: 2 September 2023 Accepted: 8 September 2023 Published: 13 September 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Article Biomarkers of Neurological Damage: From Acute Stage to Post-Acute Sequelae of COVID-19 Maria Antonella Zingaropoli 1, *, Patrizia Pasculli 1 , Christian Barbato 2 , Carla Petrella 2 , Marco Fiore 2 , Federica Dominelli 1 , Tiziana Latronico 3 , Federica Ciccone 1 , Michele Antonacci 1 , Grazia Maria Liuzzi 3 , Giuseppina Talarico 4 , Giuseppe Bruno 4 , Gioacchino Galardo 5 , Francesco Pugliese 6 , Miriam Lichtner 7,8 , Claudio Maria Mastroianni 1 , Antonio Minni 9,10,† and Maria Rosa Ciardi 1,† 1 Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome,Italy; patrizia.pasculli@uniroma1.it (P.P.); federica.dominelli@uniroma1.it (F.D.); federica.ciccone@uniroma1.it (F.C.); michele.anto26@gmail.com (M.A.); claudio.mastroianni@uniroma1.it (C.M.M.); maria.ciardi@uniroma1.it (M.R.C.) 2 Department of Sense Organs, Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Sapienza University of Rome, 00185 Rome, Italy; christian.barbato@cnr.it (C.B.); carla.petrella@cnr.it (C.P.); marco.fiore@cnr.it (M.F.) 3 Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70121 Bari, Italy; tiziana.latronico@uniba.it (T.L.); graziamaria.liuzzi@uniba.it (G.M.L.) 4 Department of Human Neuroscience, Sapienza University of Rome, 00185 Rome, Italy; giuseppina.talarico@uniroma1.it (G.T.); giuseppe.bruno@uniroma1.it (G.B.) 5 Medical Emergency Unit, Sapienza University of Rome, Policlinico Umberto I, 00161 Rome, Italy; gioacchino.galardo@uniroma1.it 6 Department of Specialist Surgery and Organ Transplantation “Paride Stefanini”, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy; f.pugliese@uniroma1.it 7 Infectious Diseases Unit, SM Goretti Hospital, Sapienza University of Rome, 00185 Latina, Italy; miriam.lichtner@uniroma1.it 8 Department of Neurosciences, Mental Health, and Sense Organs, Sapienza University of Rome, 00185 Rome, Italy 9 Department of Sensory Organs, Sapienza University of Rome, 00185 Rome, Italy; antonio.minni@uniroma1.it 10 Division of Otolaryngology-Head and Neck Surgery, ASL Rieti-Sapienza University, Ospedale San Camillo de Lellis, Viale Kennedy, 02100 Rieti, Italy * Correspondence: mariaantonella.zingaropoli@uniroma1.it † These authors contributed equally to this work. Abstract: Background: Neurological symptoms (NS) in COVID-19 are related to both acute stage and long-COVID. We explored levels of brain injury biomarkers (NfL and GFAP) and myeloid activation marker (sCD163) and their implications on the CNS. Materials and Methods: In hospitalized COVID- 19 patients plasma samples were collected at two time points: on hospital admission (baseline) and three months after hospital discharge (Tpost). Patients were stratified according to COVID-19 severity based on acute respiratory distress syndrome (ARDS) onset (severe and non-severe groups). A further stratification according to the presence of NS (with and without groups) at baseline (requiring a puncture lumbar for diagnostic purposes) and according to NS self-referred at Tpost was performed. Finally, cerebrospinal fluid (CSF) samples were collected from patients with NS present at baseline. Results: We enrolled 144 COVID-19 patients (62 female/82 male; median age [interquartile range, IQR]): 64 [55–77]) and 53 heathy donors (HD, 30 female/23 male; median age [IQR]: 64 [59–69]). At baseline, higher plasma levels of NfL, GFAP and sCD163 in COVID-19 patients compared to HD were observed (p < 0.0001, p < 0.0001 and p < 0.0001, respectively), especially in those with severe COVID-19 (p < 0.0001, p < 0.0001 and p < 0.0001, respectively). Patients with NS showed higher plasma levels of NfL, GFAP and sCD163 compared to those without (p = 0.0023, p < 0.0001 and 0.0370, respectively). At baseline, in COVID-19 patients with NS, positive correlations between CSF levels of sCD163 and CSF levels of NfL (ρ = 0.7536, p = 0.0017) and GFAP were observed (ρ = 0.7036, p = 0.0045). At Tpost, the longitudinal evaluation performed on 77 COVID-19 patients showed a significant reduction in plasma levels of NfL, GFAP and sCD163 compared to baseline (p < 0.0001, p < 0.0001 and p = 0.0413, respectively). Finally, at Tpost, in the severe group, higher plasma levels Cells 2023, 12, 2270. https://doi.org/10.3390/cells12182270 https://www.mdpi.com/journal/cells