Ahmed Abdelhak

Christian Cordano

Federico Massa

Matteo Foschi

Samir Abu-Rumeileh

Frontiers in Neurology

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TYPE EditorialPUBLISHED 11 July 2023DOI 10.3389/fneur.2023.1239750OPEN ACCESSEDITED AND REVIEWED BYMiriana d’Alessandro,University of Siena, Italy*CORRESPONDENCEAhmed Abdelhakahmed.abdelhak@ucsf.eduRECEIVED 13 June 2023ACCEPTED 01 July 2023PUBLISHED 11 July 2023CITATIONFoschi M, Abu-Rumeileh S, Massa F, Cordano Cand Abdelhak A (2023) Editorial: CSF and bloodbiomarkers in COVID-19 and otherneuroinfectious diseases.Front. Neurol. 14:1239750.doi: 10.3389/fneur.2023.1239750COPYRIGHT© 2023 Foschi, Abu-Rumeileh, Massa, Cordanoand Abdelhak. This is an open-access articledistributed under the terms of the CreativeCommons Attribution License (CC BY). The use,distribution or reproduction in other forums ispermitted, provided the original author(s) andthe copyright owner(s) are credited and thatthe original publication in this journal is cited, inaccordance with accepted academic practice.No use, distribution or reproduction ispermitted which does not comply with theseterms.Editorial: CSF and bloodbiomarkers in COVID-19 andother neuroinfectious diseasesMatteo Foschi1,2, Samir Abu-Rumeileh3, Federico Massa4,Christian Cordano4,5 and Ahmed Abdelhak5*1Department of Neuroscience, Neurology Unit, S. Maria delle Croci Hospital, AUSL Romagna, Ravenna,Italy, 2Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy,3Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany,4Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health,IRCCS Policlinico San Martino, University of Genova, Genoa, Italy, 5Department of Neurology, Universityof California, San Francisco (UCSF), San Francisco, CA, United StatesKEYWORDSCOVID-19, biomarker, diagnosis, prognosis, neuroinfectiologyEditorial on the Research TopicCSF and blood biomarkers in COVID-19 and other neuroinfectiousdiseasesThe past decades have witnessed advances in the development of ultrasensitive assaysto measure biofluid markers to improve the diagnosis and characterization of centralnervous system (CNS) involvement in primary and non-primary neurological diseases (1, 2).Neuroinfectious diseases encompass a broad spectrum of conditions where CNS injurymay result from direct pathogen invasion and systemic or compartmentalized inflammatorydamage. The recent outbreak of the COVID-19 pandemic has boosted a growing interest inthe field of biomarker application in neuroinfectious diseases. Indeed, several neurologicalmanifestations have been described in association with COVID-19, spanning from generalsymptoms (i.e., delirium, headache, dizziness, and anosmia) to CNS or peripheral nervoussystem (PNS) syndromes (i.e., encephalopathy, encephalitis, stroke, and Guillain-Barrésyndrome spectrum) diseases (1). The investigation of novel biofluid markers reflectingCNS/PNS injury is of clinical relevance given the evidence of a worse prognosis not onlyin patients with COVID-19-related major neurological manifestations (3) but even in thosewith asymptomatic/paucisymptomatic neuro-axonal injury (4).Among all available biomarkers, neurofilament light chain protein (NfL) has beenextensively studied as a biomarker of neuro-axonal injury and showed a multifaceted profileof clinical applicability, going beyond prognostication of primary neurological conditions(1). Nevertheless, blood NfL concentration measured with highly sensitive assays may beinfluenced by several physiological or paraclinical variables, including age, renal function,body mass index (BMI), and the biological matrix of the sample (EDTA-plasma or serum)(1). The latter was a significant hurdle that hampered using NfL in clinical practice andpopulation-based epidemiological studies. Rübsamen et al. investigated potential solutionsfor a better comparability of NfL concentrations measured in distinct biological matrices toharmonize findings across epidemiological studies. The authors confirmed the numericaldifferences between EDTA-plasma and serum NfL levels and derived a formula forconverting NfL values from EDTA-plasma to serum, so that reference values for NfLFrontiers inNeurology 01 frontiersin.orgFoschi et al. 10.3389/fneur.2023.1239750FIGURE 1Cerebrospinal fluid (CSF) and blood biomarkers of neuroinfectious diseases investigated in studies included in the Research Topic. ANGPT1,angiopoietin 1; APOAI, apolipoprotein AI; APOE, apolipoprotein E; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain protein; MLR,monocyte-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PTN, pleiotrophin; S100A8, s100 calcium binding protein A8. Created withBioRender.com.standardization [i.e., the recently introduced Z scores (5)] canalso be applied if only EDTA-plasma NfL levels are available.This formula represents an exciting step forward for broaderapplications of NfL in different clinical and research settings.The role of NfL was highlighted in another study ofthe present issue. Havdal et al. investigated the relationshipbetween neurological symptoms, cognitive performance (verbaland auditory working memory, verbal learning, delayed recall,and recognition), and blood biomarkers of brain injury (NfLand glial fibrillary acidic protein-GFAP) in a cohort of 405adolescents and young adults (12–25 years) with paucisymptomaticCOVID-19. They reported slightly higher levels of serum NfLand GFAP, while cognitive performance and clinical neurologicalexamination did not differ compared to age-matched non-COVID-19 controls. Neurological symptoms such as fatigue,subjective cognitive difficulties, sleep alterations, and pain werenot associated with increased serum NfL and GFAP levels norwith cognitive test results but showed a strong correlation withfemale sex and older age. These findings suggest a potentialdisconnection between self-reported neurological symptoms andbiological abnormalities in mild COVID-19. Therefore, the authorsargued that persisting clinical disturbances in these patients mightrely more on biopsychological factors than ongoing underlyingstructural CNS damage.The potential of CSF biomarkers goes beyond NfL andGFAP. Indeed, the study by Huang et al. used an unsupervisedhierarchical clustering analysis to outline a disease-specific CSFprotein profile to improve the diagnosis of tuberculous meningitis(TBM). Specifically, a combination of 3 biomarkers (APOE,APOAI, S100A8) yielded the highest ability in discriminatingTBM patients from cases with non-tubercular meningitis withan area under the curve (AUC) of 0.916 (95% sensitivity and77.5% specificity). The higher expression of APOE proteinsmay reflect a dysregulation in CNS lipids metabolism directlycaused by the pathogen. Whilst APOE proteins are mainlyreleased by astrocytes, microglia, and neurons (6), S100A8 isa proinflammatory mediator primarily expressed by neutrophilsand monocytes and involved in the maintenance of chronicinflammation. Of note, a model incorporating biomarkers relatedto different pathophysiological mechanisms reached the highestdiagnostic accuracy, thus suggesting a complex interplay ofintrinsic CNS and pathogen-induced immune activation in TBM.Similarly, the study by Zhao et al. investigated a broad panelof CSF biomarkers to identify potential diagnostic tools for post-neurosurgical bacterial meningitis (PSBM) in the CSF of 31 patientswith aneurysmal subarachnoid hemorrhage (aSAH) using Olink R©proteomic platform. A total of 15 proteins were upregulatedin patients with PSBM compared to those without, and threeproteins (PTN, CD27, ANGPT1) yielded the highest diagnosticaccuracy, thus outlining a potential distinct immunologicalprofile of PSBM.Finally, the study by He et al. evaluated the prognostic value ofcellular elements evaluated in standard CSF cytology, particularlyblood neutrophil-to-lymphocyte ratio (NTR) and monocyte-to-lymphocyte ratio (MLR) in patients with viral encephalitis(VE). The authors found significantly higher NTR and MLRat hospital admission in patients with poor (modified Rankinscale–mRS-score ≥ 2) vs. good (mRS ≤ 1) prognosis at 12-month follow-up. Additionally, increased NTR and MLR wereidentified as independent predictors of 12-month poor functionaloutcomes. These findings might improve the early identificationof critically ill VE patients who might benefit from moreintensive monitoring and early treatment escalation to preventpoor prognosis.ConclusionIn conclusion, all the articles included in this ResearchTopic provide relevant advancements to implement CSF andFrontiers inNeurology 02 frontiersin.orgFoschi et al. 10.3389/fneur.2023.1239750blood markers in the diagnostic and prognostic assessmentCOVID-19 and other neuroinfectious diseases (Figure 1)and offer novel insights into underlying pathophysiologicalprocesses. Furthermore, the study by Rübsamen et al.provides a possible solution to harmonize NfL levels whenobtained in different biological matrices, thus potentiallyrepresenting a significant step forward in the long road towardclinical validation.Author contributionsAll authors listed have made a substantial, direct, andintellectual contribution to the work and approved itfor publication.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.References1. Abu-Rumeileh S, Abdelhak A, Foschi M, D’Anna L, Russo M, Steinacker P, et al.Themultifaceted role of neurofilament light chain protein in non-primary neurologicaldiseases. Brain. (2023) 146:421–37. doi: 10.1093/brain/awac3282. Abdelhak A, Foschi M, Abu-Rumeileh S, Yue JK, D’Anna L, Huss A, et al. BloodGFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol.(2022) 18:158–72. doi: 10.1038/s41582-021-00616-33. Singh B, Lant S, Cividini S, Cattrall JWS, Goodwin LC, Benjamin L, et al.Prognostic indicators and outcomes of hospitalised COVID-19 patients withneurological disease: An individual patient data meta-analysis. PLoS ONE. (2022)17:e0263595. doi: 10.2139/ssrn.38343104. Abdelhak A, Barba L, Romoli M, Benkert P, Conversi F, D’Anna L,et al. Prognostic performance of blood neurofilament light chain proteinin hospitalized COVID-19 patients without major central nervous systemmanifestations: an individual participant data meta-analysis. J Neurol. (2023)15:1–14. doi: 10.1007/s00415-023-11768-15. Benkert P, Meier S, Schaedelin S, Manouchehrinia A, Yaldizli Ö, MaceskiA, et al. Serum neurofilament light chain for individual prognostication ofdisease activity in people with multiple sclerosis: a retrospective modelling andvalidation study. Lancet Neurol. (2022) 21:246–57. doi: 10.1016/S1474-4422(22)00009-66. Huang Y, Mahley RW. Apolipoprotein E: structure andfunction in lipid metabolism, neurobiology, and Alzheimer’sdiseases. Neurobiol Dis. (2014) 72:3–12. doi: 10.1016/j.nbd.2014.08.025Frontiers inNeurology 03 frontiersin.org

Editorial: CSF and blood biomarkers in COVID-19 and other neuroinfectious diseases

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Editorial: CSF and blood biomarkers in COVID-19 and other neuroinfectious diseases

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