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Xu Y, Yin H, Li L, Wang X, Hou Q. Covert cerebrospinal fluid dynamics dysfunction: evolution from conventional to innovative therapies. Front Neurol 2025; 16:1554813. [PMID: 40144621 PMCID: PMC11936825 DOI: 10.3389/fneur.2025.1554813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 02/27/2025] [Indexed: 03/28/2025] Open
Abstract
Cerebrospinal fluid (CSF) dynamics disorders are intricately linked to diverse neurological pathologies, though they usually are mild and covert. Contemporary insights into glymphatic system function, particularly the CSF transport, drainage, and its role in clearing metabolic waste and toxic substances in both normal and pathological states, and the pivotal role of aquaporin-4 (AQP4) in CSF-interstitial fluid (ISF) exchange, have established novel theoretical frameworks of subclinical CSF dynamics dysfunction, and have promoted the development of non-surgical therapeutic approaches for them simultaneously. This review comprehensively analyzes the advancement of non-surgical interventions for CSF dynamics disorders, emphasizing the transition from established methodologies to innovative approaches. Current non-surgical treatment strategies primarily encompass three directions: pharmacological therapy, physical therapy, and biological regulation therapy. In terms of pharmacological interventions, developments from traditional diuretics to novel small-molecule drugs show promising therapeutic potential. In physical therapy, innovative techniques such as lower body negative pressure, transcranial magnetic stimulation, and vagus nerve stimulation have provided new options for clinical practice. Meanwhile, biological regulation therapy, exemplified by recombinant VEGF-C administration, has established novel therapeutic paradigms. These therapeutic strategies have demonstrated potential in improving CSF dynamics and enhancing CSF waste elimination. Future research should focus on developing individualized treatment protocols, elucidating of therapeutic mechanisms, and assessing longitudinal outcomes. This will facilitate the development of more precise therapeutic strategies and exploration of optimized multimodal treatment combinations in handling the so-called convert CSF dynamics dysfunction.
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Affiliation(s)
- Yi Xu
- Department of Rehabilitation Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Hua Yin
- Class 6, 2020 Clinical Medicine Program, Sun Yat-Sen University, Shenzhen, China
| | - Lingge Li
- Class 2, 2020 Clinical Medicine Program, Sun Yat-Sen University, Shenzhen, China
| | - Xiaodi Wang
- Department of Neurology, Clinical Neuroscience Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Qinghua Hou
- Department of Neurology, Clinical Neuroscience Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Hong SJ, De Souza BJ, Penberthy KK, Hwang L, Procaccini DE, Kheir JN, Bembea MM. Plasma brain-related biomarkers and potential therapeutic targets in pediatric ECMO. Neurotherapeutics 2025; 22:e00521. [PMID: 39765416 PMCID: PMC11840354 DOI: 10.1016/j.neurot.2024.e00521] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 02/04/2025] Open
Abstract
Extracorporeal membrane oxygenation (ECMO) is a technique used to support severe cardiopulmonary failure. Its potential life-saving benefits are tempered by the significant risk for acute brain injury (ABI), from both primary pathophysiologic factors and ECMO-related complications through central nervous system cellular injury, blood-brain barrier dysfunction (BBB), systemic inflammation and neuroinflammation, and coagulopathy. Plasma biomarkers are an emerging tool used to stratify risk for and diagnose ABI, and prognosticate neurofunctional outcomes. Components of the neurovascular unit have been rational targets for this inquiry in ECMO. Central nervous system (CNS) neuronal and astroglial cellular-derived neuron-specific enolase (NSE), tau, glial fibrillary acidic protein (GFAP) and S100β elevations have been detected in ABI and are associated with poorer outcomes. Evidence of BBB breakdown through peripheral blood detection of CNS cellular components NSE, GFAP, and S100β, as well as evidence of elevated BBB components vWF and PDGFRβ are associated with higher mortality and worse neurofunctional outcomes. Higher concentrations of pro-inflammatory cytokines (IL-1β, IL-6, IFN-γ, TNF-α) are associated with abnormal neuroimaging, and proteomic expression panels reveal different coagulation and inflammatory responses. Abnormal coagulation profiles are common in ECMO with ongoing studies attempting to describe specific abnormalities either being causal or associated with neurologic outcomes; vWF has shown some promise. Understanding these mechanisms of injury through biomarker analysis supports potential neuroprotective strategies such as individualized blood pressure targets, judicious hypercarbia and hypoxemia correction, and immunomodulation (inhaled hydrogen and N-acetylcysteine). Further research continues to elucidate the role of biomarkers as predictors, prognosticators, and therapeutic targets.
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Affiliation(s)
- Sue J Hong
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Bradley J De Souza
- Department of Critical Care Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Kristen K Penberthy
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lisa Hwang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - John N Kheir
- Department of Cardiology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Melania M Bembea
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Eftekhari Mahabadi S, Khalifeh R, Ghods R, Wieland LS, Ghelman R, Shojaii A, Zareian A, Hosseini Yekta N. Innovative Statistical Model Uncover Effective Herbal Medicines Among Personalized Treatment Plans in Persian Medicine: A Small-Scale Study in Type 2 Diabetes. JOURNAL OF INTEGRATIVE AND COMPLEMENTARY MEDICINE 2024; 30:1217-1230. [PMID: 39084626 PMCID: PMC11659467 DOI: 10.1089/jicm.2024.0180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/02/2024]
Abstract
Objectives: In holistic medicine, developing personalized treatment plans is challenging due to the multitude of possible therapy combinations. This study introduces the use of a statistical approach to identify the most effective herbal medicines prescribed in Persian medicine (PM) in a small-scale sample of patients with type 2 diabetes mellitus (T2DM). Methods: This prospective observational cohort study was conducted with 47 patients with T2DM referred to Behesht Clinic in Tehran, Iran. A physician prescribed individualized PM treatment for T2DM and related systemic issues. The fasting blood sugar (FBS) level of each patient was recorded at initial and two follow-up visits, with visit intervals and treatment modifications determined by patient health status. Patients who completed two follow-up visits were included in the final analysis (n = 27). Data were analyzed using R software. A general linear model was assumed for the mean response, along with an exponential covariance pattern model, to manage irregularly timed measurements. Results: Two fitted models showed that, after adjusting for confounders, the use of the "Diabetes Capsule" significantly reduced the average FBS by 17.14 mmol/L (p = 0.046). For each unit increase in the consumption of "Diabetes Capsule" or "Hab-e-Amber Momiai," the average FBS decreased by 15.22 mmol/L (p = 0.015) and 14.14 mmol/L (p = 0.047), respectively. Conclusion: It is possible to observe which medications are most effective, even when treatments are applied in a holistic and personalized fashion. Preliminary studies such as these may identify promising products for testing in clinical trials conducted under standardized conditions, to inform initial choices for future personalized treatments.
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Affiliation(s)
- Samaneh Eftekhari Mahabadi
- School of Mathematics, Statistics and Computer Science, College of Science, University of Tehran, Tehran, Iran
| | - Reza Khalifeh
- School of Mathematics, Statistics and Computer Science, College of Science, University of Tehran, Tehran, Iran
| | - Roshanak Ghods
- Department of Traditional Medicine, Institute for Studies in Medical History, Persian and Complementary Medicine, School of Persian Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Ricardo Ghelman
- Department of Medicine on Primary Care, Faculty of Medicine, Federal University of Rio de Janeiro, Brazil
| | - Asie Shojaii
- Department of Traditional pharmacy, Institute for Studies in Medical History, Persian and Complementary Medicine, School of Persian Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Armin Zareian
- Departments of Public Health and Health in Disaster & Emergencies. School of Nursing, AJA University of Medical Sciences, Tehran, Iran
| | - Nafiseh Hosseini Yekta
- Department of Persian Medicine, School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran
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Friberg S, Lindblad C, Zeiler FA, Zetterberg H, Granberg T, Svenningsson P, Piehl F, Thelin EP. Fluid biomarkers of chronic traumatic brain injury. Nat Rev Neurol 2024; 20:671-684. [PMID: 39363129 DOI: 10.1038/s41582-024-01024-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 10/05/2024]
Abstract
Traumatic brain injury (TBI) is a leading cause of long-term disability across the world. Evidence for the usefulness of imaging and fluid biomarkers to predict outcomes and screen for the need to monitor complications in the acute stage is steadily increasing. Still, many people experience symptoms such as fatigue and cognitive and motor dysfunction in the chronic phase of TBI, where objective assessments for brain injury are lacking. Consensus criteria for traumatic encephalopathy syndrome, a clinical syndrome possibly associated with the neurodegenerative disease chronic traumatic encephalopathy, which is commonly associated with sports concussion, have been defined only recently. However, these criteria do not fit all individuals living with chronic consequences of TBI. The pathophysiology of chronic TBI shares many similarities with other neurodegenerative and neuroinflammatory conditions, such as Alzheimer disease. As with Alzheimer disease, advancements in fluid biomarkers represent one of the most promising paths for unravelling the chain of pathophysiological events to enable discrimination between these conditions and, with time, provide prediction modelling and therapeutic end points. This Review summarizes fluid biomarker findings in the chronic phase of TBI (≥6 months after injury) that demonstrate the involvement of inflammation, glial biology and neurodegeneration in the long-term complications of TBI. We explore how the biomarkers associate with outcome and imaging findings and aim to establish mechanistic differences in biomarker patterns between types of chronic TBI and other neurodegenerative conditions. Finally, current limitations and areas of priority for future fluid biomarker research are highlighted.
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Affiliation(s)
- Susanna Friberg
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Caroline Lindblad
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Department of Neurosurgery, Uppsala University Hospital, Uppsala, Sweden
| | - Frederick A Zeiler
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Section of Neurosurgery, Department of Surgery, University of Manitoba, Rady Faculty of Health Sciences, Winnipeg, Manitoba, Canada
- Department of Biomedical Engineering, Price Faculty of Engineering, University of Manitoba, Winnipeg, Manitoba, Canada
- Pan Am Clinic Foundation, Winnipeg, Manitoba, Canada
- Division of Anaesthesia, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Henrik Zetterberg
- UK Dementia Research Institute, University College London, London, UK
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Tobias Granberg
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Per Svenningsson
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
- Department of Basic and Clinical Neuroscience, King's College London, London, UK
| | - Fredrik Piehl
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Eric P Thelin
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
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Wallensten J, Havervall S, Power Y, Åsberg M, Borg K, Nager A, Thålin C, Mobarrez F. Oneyear longitudinal study on biomarkers of blood-brain barrier permeability in COVID-19 patients. Sci Rep 2024; 14:22735. [PMID: 39349618 PMCID: PMC11442946 DOI: 10.1038/s41598-024-73321-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 09/16/2024] [Indexed: 10/04/2024] Open
Abstract
The pathophysiology behind neurological and cognitive sequelae of COVID-19 may be related to dysfunction of the blood-brain barrier (BBB) and previous research indicate transient neuronal injury and glial activation. The aim of this study was to investigate if COVID-19 is related to increased BBB permeability by analyzing leakage of biomarkers such as astrocyte-derived extracellular vesicles (EVs) and S100B. We also investigated whether levels of these biomarkers correlated with self-reported symptoms that persisted > 2 months. The samples in this 1-year follow-up study came from an ongoing longitudinal study of unvaccinated patients hospitalized for COVID-19 at Danderyd University Hospital, Stockholm, Sweden, between April and June 2020. Blood samples were collected at baseline and 4, 8, and 12 months after hospitalization. Information on self-reported clinical symptoms was collected at follow-up visits. A total of 102 patients were enrolled, and 47 completed all follow-up measurements. Peak levels of both biomarkers were observed at 4 months in the subset of 55 patients who were measured at this timepoint. At 12 months, the biomarkers had returned to baseline levels. The biomarkers were not correlated with any of the long-term self-reported symptoms. COVID-19 is associated with transient increased BBB permeability, shown by elevated levels of astrocyte biomarkers in plasma. However, these levels return to baseline 12 months post-infection and do not correlate with long-term symptoms. Further research is needed to unravel the underlying mechanisms causing long-term symptoms in COVID-19 patients.
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Affiliation(s)
- Johanna Wallensten
- Academic Primary Health Care Centre, Region Stockholm, Solnavägen 1E, Box 45436, 104 31, Stockholm, Sweden.
- Department of Clinical Sciences, Karolinska Institute, Danderyd University Hospital, 18288, Stockholm, Sweden.
| | - Sebastian Havervall
- Department of Clinical Sciences, Karolinska Institute, Danderyd University Hospital, 18288, Stockholm, Sweden
| | - Yvonne Power
- Department of Medical Sciences, Uppsala University, 75185, Uppsala, Sweden
| | - Marie Åsberg
- Department of Clinical Sciences, Karolinska Institute, Danderyd University Hospital, 18288, Stockholm, Sweden
| | - Kristian Borg
- Department of Clinical Sciences, Karolinska Institute, Danderyd University Hospital, 18288, Stockholm, Sweden
| | - Anna Nager
- Division of Family Medicine and Primary Health Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, 17177, Stockholm, Sweden
| | - Charlotte Thålin
- Department of Clinical Sciences, Karolinska Institute, Danderyd University Hospital, 18288, Stockholm, Sweden
| | - Fariborz Mobarrez
- Department of Medical Sciences, Uppsala University, 75185, Uppsala, Sweden
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Dyhrfort P, Lindblad C, Widgren A, Virhammar J, Piehl F, Bergquist J, Al Nimer F, Rostami E. Deciphering Proteomic Expression in Inflammatory Disorders: A Mass Spectrometry Exploration Comparing Infectious, Noninfectious, and Traumatic Brain Injuries in Human Cerebrospinal Fluid. Neurotrauma Rep 2024; 5:857-873. [PMID: 39391051 PMCID: PMC11462427 DOI: 10.1089/neur.2024.0050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/12/2024] Open
Abstract
The central nervous system (CNS) evokes a complex inflammatory response to injury. Inflammatory cascades are present in traumatic, infectious, and noninfectious disorders affecting the brain. It contains a mixture of pro- and anti-inflammatory reactions involving well-known proteins, but also numerous proteins less explored in these processes. The aim of this study was to explore the distinct inflammatory response in traumatic brain injury (TBI) compared with other CNS injuries by utilization of mass-spectrometry. In total, 56 patients had their cerebrospinal fluid (CSF) analyzed with the use of mass-spectrometry. Among these, CSF was collected via an external ventricular drain (EVD) from n = 21 patients with acute TBI. The resulting protein findings were then compared with CSF obtained by lumbar puncture from n = 14 patients with noninfectious CNS disorders comprising relapsing-remitting multiple sclerosis, anti-N-methyl-d-aspartate-receptor encephalitis, acute disseminated encephalomyelitis, and n = 14 patients with progressive multifocal leukoencephalopathy, herpes simplex encephalitis, and other types of viral meningitis. We also utilized n = 7 healthy controls (HCs). In the comparison between TBI and noninfectious inflammatory CNS disorders, concentrations of 55 proteins significantly differed between the groups. Among them, 23 and 32 proteins were up- and downregulated, respectively, in the TBI group. No proteins were uniquely identified in either group. In the comparison of TBI and HC, 51 proteins were significantly different, with 24 and 27 proteins being up- and downregulated, respectively, in TBI. Two proteins (fibrinogen gamma chain and transketolase) were uniquely identified in all samples of the TBI group. Also in the last comparison, TBI versus infectious inflammatory CNS disorders, 51 proteins differed between the two groups, with 19 and 32 proteins being up- and downregulated, respectively, in TBI, and no unique proteins being identified. Due to large discrepancies between the groups compared, the following proteins were selected for further deeper analysis among those being differentially regulated: APOE, CFB, CHGA, CHI3L1, C3, FCGBP, FGA, GSN, IGFBP7, LRG1, SERPINA3, SOD3, and TTR. We found distinct proteomic profiles in the CSF of TBI patients compared with HC and different disease controls, indicating a specific interplay between inflammatory factors, metabolic response, and cell integrity. In relation to primarily infectious or inflammatory disorders, unique inflammatory pathways seem to be engaged, and could potentially serve as future treatment targets.
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Affiliation(s)
- Philip Dyhrfort
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Caroline Lindblad
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Department of Neurosurgery, Uppsala University Hospital, Uppsala, Sweden
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge University, Turku, Finland
| | - Anna Widgren
- Department of Chemistry—BMC, Analytical Chemistry and Neurochemistry, Uppsala University, Uppsala, Sweden
| | - Johan Virhammar
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Department of Neurology, Uppsala University Hospital, Uppsala, Sweden
| | - Fredrik Piehl
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Neurology, Academic Specialist Center, Stockholm, Sweden
| | - Jonas Bergquist
- Department of Chemistry—BMC, Analytical Chemistry and Neurochemistry, Uppsala University, Uppsala, Sweden
| | - Faiez Al Nimer
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Neurology, Academic Specialist Center, Stockholm, Sweden
| | - Elham Rostami
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Department of Neurosurgery, Uppsala University Hospital, Uppsala, Sweden
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Liu YX, Zhao M, Yu Y, Liu JP, Liu WJ, Yao RQ, Wang J, Yang RL, Wu Y, Dong N, Cao Y, Li SC, Zhang QH, Yan RM, Yao YM. Extracellular cold-inducible RNA-binding protein mediated neuroinflammation and neuronal apoptosis after traumatic brain injury. BURNS & TRAUMA 2024; 12:tkae004. [PMID: 38817684 PMCID: PMC11136617 DOI: 10.1093/burnst/tkae004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 01/09/2024] [Accepted: 01/25/2024] [Indexed: 06/01/2024]
Abstract
Background Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.
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Affiliation(s)
- Yu-xiao Liu
- Department of Neurosurgery, First Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Ming Zhao
- Department of Neurosurgery, First Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Yang Yu
- Department of Traditional Chinese Medical Science, Sixth Medical Center of the Chinese PLA General Hospital, Beijing 100037, People’s Republic of China
| | - Jing-peng Liu
- Department of Traditional Chinese Medical Science, Sixth Medical Center of the Chinese PLA General Hospital, Beijing 100037, People’s Republic of China
| | - Wen-jia Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 100071, People’s Republic of China
| | - Ren-qi Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Jing Wang
- Department of Obstetrics and Gynecology, Seventh Medical Center of the Chinese PLA General Hospital, Beijing 100700, People’s Republic of China
| | - Rong-li Yang
- Intensive Care Unit, Dalian Municipal Central Hospital Affiliated Dalian University of Technology, Dalian 116033, People’s Republic of China
| | - Yao Wu
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Ning Dong
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Yang Cao
- Department of Neurosurgery, First Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Shou-chun Li
- Department of Neurosurgery, First Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Qin-hong Zhang
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Run-min Yan
- Department of Neurosurgery, First Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
| | - Yong-ming Yao
- Translational Medicine Research Center, Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
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8
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Yuan HX, Zhang LN, Li G, Qiao L. Brain protective effect of dexmedetomidine vs propofol for sedation during prolonged mechanical ventilation in non-brain injured patients. World J Psychiatry 2024; 14:370-379. [PMID: 38617978 PMCID: PMC11008391 DOI: 10.5498/wjp.v14.i3.370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/21/2023] [Accepted: 01/15/2024] [Indexed: 03/19/2024] Open
Abstract
BACKGROUND Dexmedetomidine and propofol are two sedatives used for long-term sedation. It remains unclear whether dexmedetomidine provides superior cerebral protection for patients undergoing long-term mechanical ventilation. AIM To compare the neuroprotective effects of dexmedetomidine and propofol for sedation during prolonged mechanical ventilation in patients without brain injury. METHODS Patients who underwent mechanical ventilation for > 72 h were randomly assigned to receive sedation with dexmedetomidine or propofol. The Richmond Agitation and Sedation Scale (RASS) was used to evaluate sedation effects, with a target range of -3 to 0. The primary outcomes were serum levels of S100-β and neuron-specific enolase (NSE) every 24 h. The secondary outcomes were remifentanil dosage, the proportion of patients requiring rescue sedation, and the time and frequency of RASS scores within the target range. RESULTS A total of 52 and 63 patients were allocated to the dexmedetomidine group and propofol group, respectively. Baseline data were comparable between groups. No significant differences were identified between groups within the median duration of study drug infusion [52.0 (IQR: 36.0-73.5) h vs 53.0 (IQR: 37.0-72.0) h, P = 0.958], the median dose of remifentanil [4.5 (IQR: 4.0-5.0) μg/kg/h vs 4.6 (IQR: 4.0-5.0) μg/kg/h, P = 0.395], the median percentage of time in the target RASS range without rescue sedation [85.6% (IQR: 65.8%-96.6%) vs 86.7% (IQR: 72.3%-95.3), P = 0.592], and the median frequency within the target RASS range without rescue sedation [72.2% (60.8%-91.7%) vs 73.3% (60.0%-100.0%), P = 0.880]. The proportion of patients in the dexmedetomidine group who required rescue sedation was higher than in the propofol group with statistical significance (69.2% vs 50.8%, P = 0.045). Serum S100-β and NSE levels in the propofol group were higher than in the dexmedetomidine group with statistical significance during the first six and five days of mechanical ventilation, respectively (all P < 0.05). CONCLUSION Dexmedetomidine demonstrated stronger protective effects on the brain compared to propofol for long-term mechanical ventilation in patients without brain injury.
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Affiliation(s)
- Hong-Xun Yuan
- Intensive Care Unit, Peking University International Hospital, Beijing 102206, China
| | - Li-Na Zhang
- Central Operating Room, The Affiliated Beijing Chaoyang Hospital of Capital Medical University, Beijing 100020, China
| | - Gang Li
- Intensive Care Unit, Peking University International Hospital, Beijing 102206, China
| | - Li Qiao
- Intensive Care Unit, Peking University International Hospital, Beijing 102206, China
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9
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Ali HT, Sula I, AbuHamdia A, Elejla SA, Elrefaey A, Hamdar H, Elfil M. Nervous System Response to Neurotrauma: A Narrative Review of Cerebrovascular and Cellular Changes After Neurotrauma. J Mol Neurosci 2024; 74:22. [PMID: 38367075 PMCID: PMC10874332 DOI: 10.1007/s12031-024-02193-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/22/2024] [Indexed: 02/19/2024]
Abstract
Neurotrauma is a significant cause of morbidity and mortality worldwide. For instance, traumatic brain injury (TBI) causes more than 30% of all injury-related deaths in the USA annually. The underlying cause and clinical sequela vary among cases. Patients are liable to both acute and chronic changes in the nervous system after such a type of injury. Cerebrovascular disruption has the most common and serious effect in such cases because cerebrovascular autoregulation, which is one of the main determinants of cerebral perfusion pressure, can be effaced in brain injuries even in the absence of evident vascular injury. Disruption of the blood-brain barrier regulatory function may also ensue whether due to direct injury to its structure or metabolic changes. Furthermore, the autonomic nervous system (ANS) can be affected leading to sympathetic hyperactivity in many patients. On a cellular scale, the neuroinflammatory cascade medicated by the glial cells gets triggered in response to TBI. Nevertheless, cellular and molecular reactions involved in cerebrovascular repair are not fully understood yet. Most studies were done on animals with many drawbacks in interpreting results. Therefore, future studies including human subjects are necessarily needed. This review will be of relevance to clinicians and researchers interested in understanding the underlying mechanisms in neurotrauma cases and the development of proper therapies as well as those with a general interest in the neurotrauma field.
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Affiliation(s)
| | - Idris Sula
- College of Medicine, Sulaiman Al Rajhi University, Al Bukayriyah, Al Qassim, Saudi Arabia
| | - Abrar AbuHamdia
- Department of Medical Laboratory Science, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
| | | | | | - Hiba Hamdar
- Medical Learning Skills Academy, Beirut, Lebanon
- Medical University of Plovdiv, Plovdiv, Bulgaria
| | - Mohamed Elfil
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA
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Thisayakorn P, Thipakorn Y, Tantavisut S, Sirivichayakul S, Vojdani A, Maes M. Increased IgA-mediated responses to the gut paracellular pathway and blood-brain barrier proteins predict delirium due to hip fracture in older adults. Front Neurol 2024; 15:1294689. [PMID: 38379706 PMCID: PMC10876854 DOI: 10.3389/fneur.2024.1294689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 01/25/2024] [Indexed: 02/22/2024] Open
Abstract
Introduction Delirium is accompanied by immune response system activation, which may, in theory, cause a breakdown of the gut barrier and blood-brain barrier (BBB). Some results suggest that the BBB is compromised in delirium, but there is no data regarding the gut barrier. This study investigates whether delirium is associated with impaired BBB and gut barriers in elderly adults undergoing hip fracture surgery. Methods We recruited 59 older adults and measured peak Delirium Rating Scale (DRS) scores 2-3 days after surgery, and assessed plasma IgG/IgA levels (using ELISA techniques) for zonulin, occludin, claudin-6, β-catenin, actin (indicating damage to the gut paracellular pathway), claudin-5 and S100B (reflecting BBB damage), bacterial cytolethal distending toxin (CDT), LPS-binding protein (LBP), lipopolysaccharides (LPS), Porphyromonas gingivalis, and Helicobacter pylori. Results Results from univariate analyses showed that delirium is linked to increased IgA responses to all the self-epitopes and antigens listed above, except for LPS. Part of the variance (between 45-48.3%) in the peak DRS score measured 2-3 days post-surgery was explained by independent effects of IgA directed to LPS and LBP (or bacterial CDT), baseline DRS scores, and previous mild stroke. Increased IgA reactivity to the paracellular pathway and BBB proteins and bacterial antigens is significantly associated with the activation of M1 macrophage, T helper-1, and 17 cytokine profiles. Conclusion Heightened bacterial translocation, disruption of the tight and adherens junctions of the gut and BBB barriers, elevated CDT and LPS load in the bloodstream, and aberrations in cell-cell interactions may be risk factors for delirium.
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Affiliation(s)
- Paul Thisayakorn
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yanin Thipakorn
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Saran Tantavisut
- Department of Orthopedics, Hip Fracture Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sunee Sirivichayakul
- Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Aristo Vojdani
- Immunosciences Lab Inc., Los Angeles, CA, United States
- Cyrex Labs LLC, Phoenix, AZ, United States
| | - Michael Maes
- Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, China
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
- Research Institute, Medical University of Plovdiv, Plovdiv, Bulgaria
- Kyung Hee University, Seoul, Republic of Korea
- Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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11
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Biasucci DG, Sergi PG, Bilotta F, Dauri M. Diagnostic Accuracy of Procalcitonin in Bacterial Infections of the CNS: An Updated Systematic Review, Meta-Analysis, and Meta-Regression. Crit Care Med 2024; 52:112-124. [PMID: 37855662 DOI: 10.1097/ccm.0000000000006017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2023]
Abstract
OBJECTIVES To evaluate diagnostic accuracy of serum and cerebrospinal fluid (CSF) procalcitonin for diagnosing CNS bacterial infections. DATA SOURCES We searched MEDLINE, Cochrane Central Register of Controlled Trials, and International Web of Science databases from January 1, 2016, to September 30, 2022. STUDY SELECTION Randomized controlled trials and observational studies, either prospective or retrospective, focusing on procalcitonin as a biomarker for CNS infections. DATA EXTRACTION We screened and extracted studies independently and in duplicate. We assessed risk of bias using the revised Quality Assessment for Studies of Diagnostic Accuracy tool. Data for diagnostic sensitivity and specificity were pooled using the bivariate or hierarchical model, as appropriate. DATA SYNTHESIS Of 5,347 citations identified, 23 studies were included. Overall, CSF procalcitonin showed slightly higher pooled sensitivity, specificity, and positive likelihood ratio compared with serum procalcitonin. In adults, pooled sensitivity of CSF procalcitonin was 0.89 (95% CI, 0.71-0.96), specificity 0.81 (95% CI, 0.66-0.91); pooled sensitivity of serum procalcitonin was 0.82 (95% CI, 0.58-0.94), specificity 0.77 (95% CI, 0.60-0.89). In children, pooled sensitivity of CSF procalcitonin was 0.96 (95% CI, 0.88-0.99), specificity 0.91 (95% CI, 0.72-0.97); pooled sensitivity of serum procalcitonin was 0.90 (95% CI, 0.75-0.97), specificity 0.83 (95% CI, 0.67-0.92). In post-neurosurgical patients, pooled sensitivity of CSF procalcitonin was 0.82 (95% CI, 0.53-0.95), specificity 0.81 (95% CI, 0.63-0.91); pooled sensitivity of serum procalcitonin was 0.65 (95% CI, 0.33-0.88), specificity 0.61 (95% CI, 0.41-0.78). Logistic regression revealed between-study heterogeneity higher for serum than CSF procalcitonin. For the latter, threshold variability was found as source of heterogeneity. CONCLUSIONS In children and critical post-neurosurgical patients, CSF procalcitonin gains superior sensitivity and specificity compared with serum procalcitonin. Overall, CSF procalcitonin appears to have a higher pooled positive likelihood ratio compared with serum procalcitonin.
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Affiliation(s)
- Daniele Guerino Biasucci
- Department of Clinical Science and Translational Medicine, Faculty of Medicine and Surgery, "Tor Vergata" University of Rome, Rome, Italy
| | | | - Federico Bilotta
- Department of General and Specialistic Surgery, "La Sapienza" University, Rome, Italy
| | - Mario Dauri
- Department of Clinical Science and Translational Medicine, Faculty of Medicine and Surgery, "Tor Vergata" University of Rome, Rome, Italy
- Emergency Department, "Tor Vergata" University Hospital, Rome, Italy
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12
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Hossain I, Marklund N, Czeiter E, Hutchinson P, Buki A. Blood biomarkers for traumatic brain injury: A narrative review of current evidence. BRAIN & SPINE 2023; 4:102735. [PMID: 38510630 PMCID: PMC10951700 DOI: 10.1016/j.bas.2023.102735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 12/05/2023] [Accepted: 12/11/2023] [Indexed: 03/22/2024]
Abstract
Introduction A blood-based biomarker (BBBM) test could help to better stratify patients with traumatic brain injury (TBI), reduce unnecessary imaging, to detect and treat secondary insults, predict outcomes, and monitor treatment effects and quality of care. Research question What evidence is available for clinical applications of BBBMs in TBI and how to advance this field? Material and methods This narrative review discusses the potential clinical applications of core BBBMs in TBI. A literature search in PubMed, Scopus, and ISI Web of Knowledge focused on articles in English with the words "traumatic brain injury" together with the words "blood biomarkers", "diagnostics", "outcome prediction", "extracranial injury" and "assay method" alone-, or in combination. Results Glial fibrillary acidic protein (GFAP) combined with Ubiquitin C-terminal hydrolase-L1(UCH-L1) has received FDA clearance to aid computed tomography (CT)-detection of brain lesions in mild (m) TBI. Application of S100B led to reduction of head CT scans. GFAP may also predict magnetic resonance imaging (MRI) abnormalities in CT-negative cases of TBI. Further, UCH-L1, S100B, Neurofilament light (NF-L), and total tau showed value for predicting mortality or unfavourable outcome. Nevertheless, biomarkers have less role in outcome prediction in mTBI. S100B could serve as a tool in the multimodality monitoring of patients in the neurointensive care unit. Discussion and conclusion Largescale systematic studies are required to explore the kinetics of BBBMs and their use in multiple clinical groups. Assay development/cross validation should advance the generalizability of those results which implicated GFAP, S100B and NF-L as most promising biomarkers in the diagnostics of TBI.
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Affiliation(s)
- Iftakher Hossain
- Neurocenter, Department of Neurosurgery, Turku University Hospital, Turku, Finland
- Department of Clinical Neurosciences, Neurosurgery Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
- Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Niklas Marklund
- Department of Clinical Sciences Lund, Neurosurgery, Lund University, Department of Neurosurgery, Skåne University Hospital, Lund, Sweden
| | - Endre Czeiter
- Department of Neurosurgery, Medical School, Neurotrauma Research Group, Szentagothai Research Centre, And HUN-REN-PTE Clinical Neuroscience MR Research Group, University of Pecs, Pecs, Hungary
| | - Peter Hutchinson
- Department of Clinical Neurosciences, Neurosurgery Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Andras Buki
- Department of Neurosurgery, University of Örebro, Örebro, Sweden
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13
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Zhang X, Zhang Q, Wu S, Hua K, Cui Y. A biosensor for S100B detection based on PSS-MA-GoldMag-LFIA in early clinical diagnosis of brain damage. Analyst 2023; 148:6369-6374. [PMID: 37974479 DOI: 10.1039/d2an01562e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
S100B is an essential biomarker in the early diagnosis and treatment monitoring of brain injury. However, the traditional clinical diagnostic assay for S100B detection requires a complex operation or large equipment, which limits its application for rapid point-of-care tests (POCT). This study aimed to establish a lateral-flow immunoassay (LFIA) strip test system for S100B determination. PSS-MA-GoldMag nanoparticles were conjugated with anti-S100B antibodies as probes. Using this antibody-nanoparticle composite, an LFIA system based on magnetic quantification was established for S100B detection. For the evaluation of the performance of this LFIA system in clinical practice, 216 clinical samples were assayed using the LFIA test system and a commercial ECLI kit. Using the LFIA system, reliable results could be obtained in 30 min with a detection limit of 0.05 ng mL-1. The coefficient of variation (CV) was <13.8% and <14.03% for intra- and inter-assay precision, respectively. The recoveries were between 95.1 and 107.3%. The relative deviation of the interference experiments was <10%. In the analysis of clinical samples, the result indicated that the sera level of S100B in the detection group did not correlate with gender (p = 0.564 > 0.05) or age (p = 0.083 > 0.05). There is a good correlation between the novel method and the Elecsys®, with a determination coefficient of R2 0.9566, p > 0.05. The Bland-Altman analysis between the two ways shows that the 95% confidence bands between the two methods in measuring S100B were -0.27 ng mL-1 to +0.29 ng mL-1 with a mean difference of +0.006 ng mL-1. These results indicated that the novel LFIA system could be a simple, rapid, convenient, and accurate method for S100B determination.
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Affiliation(s)
- Xiaomei Zhang
- College of Life Sciences, Northwest University, Xi'an, 710069, China
- College of Agronomy, Henan University of Science and Technology, Luoyang 471003, China
| | - Qinlu Zhang
- School of Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Songdi Wu
- Xi'an City First Hospital, Xi'an, 710068, China
| | - Kai Hua
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Yali Cui
- College of Life Sciences, Northwest University, Xi'an, 710069, China
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14
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Agoston DV, Helmy A. Fluid-Based Protein Biomarkers in Traumatic Brain Injury: The View from the Bedside. Int J Mol Sci 2023; 24:16267. [PMID: 38003454 PMCID: PMC10671762 DOI: 10.3390/ijms242216267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/07/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
There has been an explosion of research into biofluid (blood, cerebrospinal fluid, CSF)-based protein biomarkers in traumatic brain injury (TBI) over the past decade. The availability of very large datasets, such as CENTRE-TBI and TRACK-TBI, allows for correlation of blood- and CSF-based molecular (protein), radiological (structural) and clinical (physiological) marker data to adverse clinical outcomes. The quality of a given biomarker has often been framed in relation to the predictive power on the outcome quantified from the area under the Receiver Operating Characteristic (ROC) curve. However, this does not in itself provide clinical utility but reflects a statistical association in any given population between one or more variables and clinical outcome. It is not currently established how to incorporate and integrate biofluid-based biomarker data into patient management because there is no standardized role for such data in clinical decision making. We review the current status of biomarker research and discuss how we can integrate existing markers into current clinical practice and what additional biomarkers do we need to improve diagnoses and to guide therapy and to assess treatment efficacy. Furthermore, we argue for employing machine learning (ML) capabilities to integrate the protein biomarker data with other established, routinely used clinical diagnostic tools, to provide the clinician with actionable information to guide medical intervention.
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Affiliation(s)
- Denes V. Agoston
- Department of Anatomy, Physiology and Genetic, School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA
| | - Adel Helmy
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK;
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15
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Gayger-Dias V, Vizuete AFK, Rodrigues L, Wartchow KM, Bobermin L, Leite MC, Quincozes-Santos A, Kleindienst A, Gonçalves CA. How S100B crosses brain barriers and why it is considered a peripheral marker of brain injury. Exp Biol Med (Maywood) 2023; 248:2109-2119. [PMID: 38058025 PMCID: PMC10800124 DOI: 10.1177/15353702231214260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2023] Open
Abstract
S100B is a 21-kDa protein that is produced and secreted by astrocytes and widely used as a marker of brain injury in clinical and experimental studies. The majority of these studies are based on measurements in blood serum, assuming an associated increase in cerebrospinal fluid and a rupture of the blood-brain barrier (BBB). Moreover, extracerebral sources of S100B are often underestimated. Herein, we will review these interpretations and discuss the routes by which S100B, produced by astrocytes, reaches the circulatory system. We discuss the concept of S100B as an alarmin and its dual activity as an inflammatory and neurotrophic molecule. Furthermore, we emphasize the lack of data supporting the idea that S100B acts as a marker of BBB rupture, and the need to include the glymphatic system in the interpretations of serum changes of S100B. The review is also dedicated to valorizing extracerebral sources of S100B, particularly adipocytes. Furthermore, S100B per se may have direct and indirect modulating roles in brain barriers: on the tight junctions that regulate paracellular transport; on the expression of its receptor, RAGE, which is involved in transcellular protein transport; and on aquaporin-4, a key protein in the glymphatic system that is responsible for the clearance of extracellular proteins from the central nervous system. We hope that the data on S100B, discussed here, will be useful and that it will translate into further health benefits in medical practice.
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Affiliation(s)
- Vitor Gayger-Dias
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Adriana FK Vizuete
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Letícia Rodrigues
- Graduate Program in Neurosciences, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Krista Minéia Wartchow
- Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, NY 10044, USA
| | - Larissa Bobermin
- Graduate Program in Neurosciences, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Marina Concli Leite
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - André Quincozes-Santos
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
| | - Andrea Kleindienst
- Department of Neurosurgery, Friedrich-Alexander University, 91054 Erlangen, Germany
| | - Carlos-Alberto Gonçalves
- Graduate Program in Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre 90.035-003, Brazil
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16
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Peters ME, Lyketsos CG. The glymphatic system's role in traumatic brain injury-related neurodegeneration. Mol Psychiatry 2023; 28:2707-2715. [PMID: 37185960 DOI: 10.1038/s41380-023-02070-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 04/03/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023]
Abstract
In at least some individuals who suffer a traumatic brain injury (TBI), there exists a risk of future neurodegenerative illness. This review focuses on the association between the brain-based paravascular drainage pathway known as the "glymphatic system" and TBI-related neurodegeneration. The glymphatic system is composed of cerebrospinal fluid (CSF) flowing into the brain parenchyma along paravascular spaces surrounding penetrating arterioles where it mixes with interstitial fluid (ISF) before being cleared along paravenous drainage pathways. Aquaporin-4 (AQP4) water channels on astrocytic end-feet appear essential for the functioning of this system. The current literature linking glymphatic system disruption and TBI-related neurodegeneration is largely based on murine models with existing human research focused on the need for biomarkers of glymphatic system function (e.g., neuroimaging modalities). Key findings from the existing literature include evidence of glymphatic system flow disruption following TBI, mechanisms of this decreased flow (i.e., AQP4 depolarization), and evidence of protein accumulation and deposition (e.g., amyloid β, tau). The same studies suggest that glymphatic dysfunction leads to subsequent neurodegeneration, cognitive decline, and/or behavioral change although replication in humans is needed. Identified emerging topics from the literature are as follows: link between TBI, sleep, and glymphatic system dysfunction; influence of glymphatic system disruption on TBI biomarkers; and development of novel treatments for glymphatic system disruption following TBI. Although a burgeoning field, more research is needed to elucidate the role of glymphatic system disruption in TBI-related neurodegeneration.
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Affiliation(s)
- Matthew E Peters
- Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Constantine G Lyketsos
- Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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17
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Bell A, Hewins B, Bishop C, Fortin A, Wang J, Creamer JL, Collen J, Werner JK. Traumatic Brain Injury, Sleep, and Melatonin-Intrinsic Changes with Therapeutic Potential. Clocks Sleep 2023; 5:177-203. [PMID: 37092428 PMCID: PMC10123665 DOI: 10.3390/clockssleep5020016] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/25/2023] Open
Abstract
Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity in the United States and is associated with numerous chronic sequelae long after the point of injury. One of the most common long-term complaints in patients with TBI is sleep dysfunction. It is reported that alterations in melatonin follow TBI and may be linked with various sleep and circadian disorders directly (via cellular signaling) or indirectly (via free radicals and inflammatory signaling). Work over the past two decades has contributed to our understanding of the role of melatonin as a sleep regulator and neuroprotective anti-inflammatory agent. Although there is increasing interest in the treatment of insomnia following TBI, a lack of standardization and rigor in melatonin research has left behind a trail of non-generalizable data and ambiguous treatment recommendations. This narrative review describes the underlying biochemical properties of melatonin as they are relevant to TBI. We also discuss potential benefits and a path forward regarding the therapeutic management of TBI with melatonin treatment, including its role as a neuroprotectant, a somnogen, and a modulator of the circadian rhythm.
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Affiliation(s)
- Allen Bell
- Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
| | - Bryson Hewins
- School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (B.H.)
| | - Courtney Bishop
- School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (B.H.)
| | - Amanda Fortin
- School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (B.H.)
| | - Jonathan Wang
- School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (B.H.)
| | | | - Jacob Collen
- Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
- School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (B.H.)
| | - J. Kent Werner
- Walter Reed National Military Medical Center, Bethesda, MD 20814, USA
- School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (B.H.)
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18
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Stacey BS, Hoiland RL, Caldwell HG, Howe CA, Vermeulen T, Tymko MM, Vizcardo‐Galindo GA, Bermudez D, Figueroa‐Mujíica RJ, Gasho C, Tuaillon E, Hirtz C, Lehmann S, Marchi N, Tsukamoto H, Villafuerte FC, Ainslie PN, Bailey DM. Lifelong exposure to high-altitude hypoxia in humans is associated with improved redox homeostasis and structural-functional adaptations of the neurovascular unit. J Physiol 2023; 601:1095-1120. [PMID: 36633375 PMCID: PMC10952731 DOI: 10.1113/jp283362] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 12/20/2022] [Indexed: 01/13/2023] Open
Abstract
High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.
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Affiliation(s)
- Benjamin S. Stacey
- Neurovascular Research Laboratory, Faculty of Life Sciences and EducationUniversity of South WalesPontypriddUK
| | - Ryan L. Hoiland
- Department of Anaesthesiology, Pharmacology and Therapeutics, Vancouver General HospitalUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Department of Cellular and Physiological Sciences, Faculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Hannah G. Caldwell
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
| | - Connor A. Howe
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
| | - Tyler Vermeulen
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
| | - Michael M. Tymko
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
- Faculty of Kinesiology, Sport, and RecreationUniversity of AlbertaEdmontonAlbertaCanada
- Department of Medicine, Faculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Gustavo A. Vizcardo‐Galindo
- Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y FilosofíaUniversidad Peruana Cayetano HerediaLima 31Peru
| | - Daniella Bermudez
- Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y FilosofíaUniversidad Peruana Cayetano HerediaLima 31Peru
| | - Rómulo J. Figueroa‐Mujíica
- Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y FilosofíaUniversidad Peruana Cayetano HerediaLima 31Peru
| | - Christopher Gasho
- Division of Pulmonary and Critical CareLoma Linda University School of MedicineLoma LindaCAUSA
| | - Edouard Tuaillon
- Department of Infectious DiseasesUniversity of MontpellierMontpellierFrance
| | - Christophe Hirtz
- LBPC‐PPCUniversité de Montpellier, IRMB CHU de Montpellier, INM INSERMMontpellierFrance
| | - Sylvain Lehmann
- LBPC‐PPCUniversité de Montpellier, IRMB CHU de Montpellier, INM INSERMMontpellierFrance
| | - Nicola Marchi
- Laboratory of Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional GenomicsUniversity of MontpellierMontpellierFrance
| | - Hayato Tsukamoto
- Faculty of Sport and Health ScienceRitsumeikan UniversityKusatsuShigaJapan
| | - Francisco C. Villafuerte
- Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y FilosofíaUniversidad Peruana Cayetano HerediaLima 31Peru
| | - Philip N. Ainslie
- Neurovascular Research Laboratory, Faculty of Life Sciences and EducationUniversity of South WalesPontypriddUK
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
| | - Damian M. Bailey
- Neurovascular Research Laboratory, Faculty of Life Sciences and EducationUniversity of South WalesPontypriddUK
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19
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Oris C, Durif J, Rouzaire M, Pereira B, Bouvier D, Kahouadji S, Abbot M, Brailova M, Lehmann S, Hirtz C, Decq P, Dusfour B, Marchi N, Sapin V. Blood Biomarkers for Return to Play after Concussion in Professional Rugby Players. J Neurotrauma 2023; 40:283-295. [PMID: 36047487 DOI: 10.1089/neu.2022.0148] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
We prospectively evaluated a panel of seven blood biomarkers (S100 calcium-binding protein B [S100B], neuron specific enolase [NSE], spectrin breakdown products [SBDP], ubiquitin C-terminal hydrolase L1 [UCHL1], glial fibrillary acidic protein [GFAP], neurofilament light chain [NFL], and tubulin-associated unit [Tau]) for sport-related concussion (SRC) in a large multi-centric cohort of 496 professional rugby players from 14 French elite teams. Players were sampled twice during the season (beginning and end) away from any sport practice. From these two baseline samples, we evaluated the intra-individual variability to establish the effect of rugby on blood biomarkers over a season. Only S100B and GFAP remained stable over the course of a season. During the period of the study, a total of 45 SRC cases was reported for 42 players. In 45 SRCs, the head injury assessment (HIA) process was performed and blood collection was realized 36 h after the concussion (HIA-3 stage). For each biomarker, raw concentrations measured 36 h after SRC were not significantly different between players with a non-resolutive SRC (n = 28) and those with a resolutive SRC (n = 17; p between 0.06 and 0.92). In a second step, blood concentrations measured 36 h after SRC were expressed according to the basal concentrations as an individual percentage change (PCH36[%]), calculated as follows: PCH36 = 100 × (([Biomarker]36h - [Biomarker]basal)/[Biomarker]basal). S100B and NFL concentrations expressed as PCH36[%] were significantly different between non-resolutive and resolutive SRCs (p = 0.006 and 0.01 respectively), with a positive delta found in non-resolutive SRCs. Among the two biomarkers, it is important to note that only the S100B protein was stable during the season. In the context of our study, during HIA-3 assessment, S100B seems to perform better than NSE, SBDP, UCHL1, GFAP, NFL, and Tau as biomarker for SRC. From a clinical standpoint, the S100B modification over baseline may be valuable, at 36 h after concussion to distinguish non-resolutive SRC from resolutive SRC.
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Affiliation(s)
- Charlotte Oris
- Department of Biochemistry and Molecular Genetics, University Hospital, Clermont-Ferrand, France
- Clermont Auvergne University, CNRS, INSERM, iGReD, Clermont-Ferrand, France
| | - Julie Durif
- Department of Biochemistry and Molecular Genetics, University Hospital, Clermont-Ferrand, France
| | - Marion Rouzaire
- Department of Biochemistry and Molecular Genetics, University Hospital, Clermont-Ferrand, France
| | - Bruno Pereira
- Biostatistics unit (DRCI) Department, University Hospital, Clermont-Ferrand, France
| | - Damien Bouvier
- Department of Biochemistry and Molecular Genetics, University Hospital, Clermont-Ferrand, France
- Clermont Auvergne University, CNRS, INSERM, iGReD, Clermont-Ferrand, France
| | - Samy Kahouadji
- Department of Biochemistry and Molecular Genetics, University Hospital, Clermont-Ferrand, France
- Clermont Auvergne University, CNRS, INSERM, iGReD, Clermont-Ferrand, France
| | - Mathieu Abbot
- Department of Sport Medicine and Functional Explorations, University Hospital, Clermont-Ferrand, France
| | - Marina Brailova
- Department of Biochemistry and Molecular Genetics, University Hospital, Clermont-Ferrand, France
| | | | | | - Philippe Decq
- Neurosurgery Department, Beaujon Hospital, Paris University, Paris, France
- Assistance Publique-Hôpitaux de Paris, Clichy, France
- Institut de Biomécanique Humaine Georges Charpak, Arts et Métiers ParisTech, Paris, France
| | - Bernard Dusfour
- Medical Committee, French National Rugby League, Paris, France
| | - Nicola Marchi
- Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional Genomics (UMR 5203 CNRS-U 1191 INSERM, University of Montpellier), Montpellier, France
| | - Vincent Sapin
- Department of Biochemistry and Molecular Genetics, University Hospital, Clermont-Ferrand, France
- Clermont Auvergne University, CNRS, INSERM, iGReD, Clermont-Ferrand, France
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20
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Lin IH, Kamnaksh A, Aniceto R, McCullough J, Bekdash R, Eklund M, Ghatan PH, Risling M, Svensson M, Bellander BM, Nelson DW, Thelin EP, Agoston DV. Time-Dependent Changes in the Biofluid Levels of Neural Injury Markers in Severe Traumatic Brain Injury Patients-Cerebrospinal Fluid and Cerebral Microdialysates: A Longitudinal Prospective Pilot Study. Neurotrauma Rep 2023; 4:107-117. [PMID: 36895820 PMCID: PMC9989523 DOI: 10.1089/neur.2022.0076] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023] Open
Abstract
Monitoring protein biomarker levels in the cerebrospinal fluid (CSF) can help assess injury severity and outcome after traumatic brain injury (TBI). Determining injury-induced changes in the proteome of brain extracellular fluid (bECF) can more closely reflect changes in the brain parenchyma, but bECF is not routinely available. The aim of this pilot study was to compare time-dependent changes of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), total Tau, and phosphorylated Tau (p-Tau) levels in matching CSF and bECF samples collected at 1, 3, and 5 days post-injury from severe TBI patients (n = 7; GCS 3-8) using microcapillary-based western analysis. We found that time-dependent changes in CSF and bECF levels were most pronounced for S100B and NSE, but there was substantial patient-to-patient variability. Importantly, the temporal pattern of biomarker changes in CSF and bECF samples showed similar trends. We also detected two different immunoreactive forms of S100B in both CSF and bECF samples, but the contribution of the different immunoreactive forms to total immunoreactivity varied from patient to patient and time point to time point. Our study is limited, but it illustrates the value of both quantitative and qualitative analysis of protein biomarkers and the importance of serial sampling for biofluid analysis after severe TBI.
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Affiliation(s)
- I-Hsuan Lin
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Alaa Kamnaksh
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Roxanne Aniceto
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Jesse McCullough
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Ramsey Bekdash
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Michael Eklund
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Per Hamid Ghatan
- Department of Neuroscience, Uppsala University Hospital, Uppsala, Sweden
| | - Mårten Risling
- Department of Neuroscience, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Mikael Svensson
- Department of Clinical Neuroscience, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.,Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
| | - Bo-Michael Bellander
- Department of Clinical Neuroscience, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.,Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
| | - David W Nelson
- Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.,Section of Perioperative Medicine and Intensive Care, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Eric Peter Thelin
- Department of Clinical Neuroscience, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.,Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Denes V Agoston
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
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21
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Shultz SR, Shah AD, Huang C, Dill LK, Schittenhelm RB, Morganti-Kossmann MC, Semple BD. Temporal proteomics of human cerebrospinal fluid after severe traumatic brain injury. J Neuroinflammation 2022; 19:291. [PMID: 36482407 PMCID: PMC9730674 DOI: 10.1186/s12974-022-02654-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022] Open
Abstract
The pathophysiology of traumatic brain injury (TBI) requires further characterization to fully elucidate changes in molecular pathways. Cerebrospinal fluid (CSF) provides a rich repository of brain-associated proteins. In this retrospective observational study, we implemented high-resolution mass spectrometry to evaluate changes to the CSF proteome after severe TBI. 91 CSF samples were analyzed with mass spectrometry, collected from 16 patients with severe TBI (mean 32 yrs; 81% male) on day 0, 1, 2, 4, 7 and/or 10 post-injury (8-16 samples/timepoint) and compared to CSF obtained from 11 non-injured controls. We quantified 1152 proteins with mass spectrometry, of which approximately 80% were associated with CSF. 1083 proteins were differentially regulated after TBI compared to control samples. The most highly-upregulated proteins at each timepoint included neutrophil elastase, myeloperoxidase, cathepsin G, matrix metalloproteinase-8, and S100 calcium-binding proteins A8, A9 and A12-all proteins involved in neutrophil activation, recruitment, and degranulation. Pathway enrichment analysis confirmed the robust upregulation of proteins associated with innate immune responses. Conversely, downregulated pathways included those involved in nervous system development, and several proteins not previously identified after TBI such as testican-1 and latrophilin-1. We also identified 7 proteins (GM2A, Calsyntenin 1, FAT2, GANAB, Lumican, NPTX1, SFRP2) positively associated with an unfavorable outcome at 6 months post-injury. Together, these findings highlight the robust innate immune response that occurs after severe TBI, supporting future studies to target neutrophil-related processes. In addition, the novel proteins we identified to be differentially regulated by severe TBI warrant further investigation as potential biomarkers of brain damage or therapeutic targets.
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Affiliation(s)
- Sandy R. Shultz
- grid.1002.30000 0004 1936 7857Department of Neuroscience, Monash University, Melbourne, VIC Australia ,grid.267362.40000 0004 0432 5259Alfred Health, Prahran, VIC Australia ,grid.1008.90000 0001 2179 088XDepartment of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC Australia ,grid.267756.70000 0001 2183 6550Health and Human Services, Vancouver Island University, Nanaimo, Canada
| | - Anup D. Shah
- grid.1002.30000 0004 1936 7857Monash Proteomics and Metabolomics Facility, Monash University, Clayton, VIC Australia ,grid.1002.30000 0004 1936 7857Monash Bioinformatics Platform, Monash University, Clayton, VIC Australia
| | - Cheng Huang
- grid.1002.30000 0004 1936 7857Monash Proteomics and Metabolomics Facility, Monash University, Clayton, VIC Australia
| | - Larissa K. Dill
- grid.1002.30000 0004 1936 7857Department of Neuroscience, Monash University, Melbourne, VIC Australia ,grid.267362.40000 0004 0432 5259Alfred Health, Prahran, VIC Australia ,grid.482226.80000 0004 0437 5686The Perron Institute for Neurological and Translational Science, Nedlands, WA 6009 Australia
| | - Ralf B. Schittenhelm
- grid.1002.30000 0004 1936 7857Monash Proteomics and Metabolomics Facility, Monash University, Clayton, VIC Australia
| | - M. Cristina Morganti-Kossmann
- grid.1002.30000 0004 1936 7857Department of Epidemiology & Preventive Medicine, Monash University, Prahran, VIC Australia ,grid.427785.b0000 0001 0664 3531Department of Child Health, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ USA ,grid.134563.60000 0001 2168 186XUniversity of Arizona College of Medicine, Phoenix, AZ USA
| | - Bridgette D. Semple
- grid.1002.30000 0004 1936 7857Department of Neuroscience, Monash University, Melbourne, VIC Australia ,grid.267362.40000 0004 0432 5259Alfred Health, Prahran, VIC Australia ,grid.1008.90000 0001 2179 088XDepartment of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC Australia
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22
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Heiskanen M, Jääskeläinen O, Manninen E, Das Gupta S, Andrade P, Ciszek R, Gröhn O, Herukka SK, Puhakka N, Pitkänen A. Plasma Neurofilament Light Chain (NF-L) Is a Prognostic Biomarker for Cortical Damage Evolution but Not for Cognitive Impairment or Epileptogenesis Following Experimental TBI. Int J Mol Sci 2022; 23:ijms232315208. [PMID: 36499527 PMCID: PMC9736117 DOI: 10.3390/ijms232315208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/08/2022] Open
Abstract
Plasma neurofilament light chain (NF-L) levels were assessed as a diagnostic biomarker for traumatic brain injury (TBI) and as a prognostic biomarker for somatomotor recovery, cognitive decline, and epileptogenesis. Rats with severe TBI induced by lateral fluid-percussion injury (n = 26, 13 with and 13 without epilepsy) or sham-operation (n = 8) were studied. During a 6-month follow-up, rats underwent magnetic resonance imaging (MRI) (day (D) 2, D7, and D21), composite neuroscore (D2, D6, and D14), Morris-water maze (D35−D39), and a 1-month-long video-electroencephalogram to detect unprovoked seizures during the 6th month. Plasma NF-L levels were assessed using a single-molecule assay at baseline (i.e., naïve animals) and on D2, D9, and D178 after TBI or a sham operation. Plasma NF-L levels were 483-fold higher on D2 (5072.0 ± 2007.0 pg/mL), 89-fold higher on D9 (930.3 ± 306.4 pg/mL), and 3-fold higher on D176 32.2 ± 8.9 pg/mL after TBI compared with baseline (10.5 ± 2.6 pg/mL; all p < 0.001). Plasma NF-L levels distinguished TBI rats from naïve animals at all time-points examined (area under the curve [AUC] 1.0, p < 0.001), and from sham-operated controls on D2 (AUC 1.0, p < 0.001). Plasma NF-L increases on D2 were associated with somatomotor impairment severity (ρ = −0.480, p < 0.05) and the cortical lesion extent in MRI (ρ = 0.401, p < 0.05). Plasma NF-L increases on D2 or D9 were associated with the cortical lesion extent in histologic sections at 6 months post-injury (ρ = 0.437 for D2; ρ = 0.393 for D9, p < 0.05). Plasma NF-L levels, however, did not predict somatomotor recovery, cognitive decline, or epileptogenesis (p > 0.05). Plasma NF-L levels represent a promising noninvasive translational diagnostic biomarker for acute TBI and a prognostic biomarker for post-injury somatomotor impairment and long-term structural brain damage.
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Affiliation(s)
- Mette Heiskanen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Olli Jääskeläinen
- Institute of Clinical Medicine/Neurology, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Eppu Manninen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Shalini Das Gupta
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Pedro Andrade
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Robert Ciszek
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Olli Gröhn
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Sanna-Kaisa Herukka
- Institute of Clinical Medicine/Neurology, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
- Department of Neurology, Kuopio University Hospital, P.O. Box 1777, 70211 Kuopio, Finland
| | - Noora Puhakka
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
| | - Asla Pitkänen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
- Correspondence:
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23
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Wichmann TO, Kasch H, Dyrskog S, Høy K, Møller BK, Krog J, Hviid CVB, Hoffmann HJ, Rasmussen MM. The inflammatory response and blood-spinal cord barrier integrity in traumatic spinal cord injury: a prospective pilot study. Acta Neurochir (Wien) 2022; 164:3143-3153. [PMID: 36190569 DOI: 10.1007/s00701-022-05369-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 09/07/2022] [Indexed: 02/01/2023]
Abstract
PURPOSE Triggering of inflammatory responses and disruption of blood-spinal cord barrier (BSCB) integrity are considered pivotal events in the pathophysiology of traumatic spinal cord injury (TSCI). Yet, these events are poorly understood and described in humans. This study aims to describe inflammatory responses and BSCB integrity in human TSCI. METHODS Fifteen TSCI patients and fifteen non-TSCI patients were prospectively recruited from Aarhus University Hospital, Denmark. Peripheral blood (PB) and cerebrospinal fluid (CSF) were collected at median day 0 [IQR: 1], median day 9 [IQR: 2], and median day 148 [IQR: 49] after injury. PB and CSF were analyzed for immune cells by flow cytometry, cytokines by multiplex immunoassay, and BSCB integrity by IgG Index. RESULTS Eleven TSCI patients completed follow-up. Results showed alterations in innate and adaptive immune cell counts over time. TSCI patients had significantly increased cytokine concentrations in CSF at the first and second follow-up, while only concentrations of interleukin (IL)-4, IL-8, and tumor necrosis factor-α remained significantly increased at the third follow-up. In PB, TSCI patients had significantly increased IL-6, IL-8, and IL-10 concentrations and significantly decreased interferon-γ concentrations at the first follow-up. Results further showed increased IgG Index indicative of BSCB disruption in seven TSCI patients at the first follow-up, five TSCI patients at the second follow-up, and two patients at the third follow-up. CONCLUSIONS Our results suggest that TSCI mainly triggers innate inflammatory responses that resolves over time, although with some degree of non-resolving inflammation, particularly in CSF. Our results cannot confirm BSCB disruption in all TSCI patients.
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Affiliation(s)
- Thea Overgaard Wichmann
- Dept. Neurosurgery, Cense-Spine, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 165 8200 Aarhus N, Aarhus, Denmark.
| | - Helge Kasch
- Dept. Neurology, Aarhus University Hospital, Aarhus, Denmark.,Dept. of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Stig Dyrskog
- Dept. Intensive Care, Aarhus University Hospital, Aarhus, Denmark
| | - Kristian Høy
- Dept. of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Dept. Orthopaedic Surgery - Spine section, Aarhus University Hospital, Aarhus, Denmark
| | - Bjarne Kuno Møller
- Dept. of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| | - Jan Krog
- Dept. Anaesthesiology, Aarhus University Hospital, Aarhus, Denmark
| | - Claus Vinter Bødker Hviid
- Dept. Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.,Dept. Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Hans Jürgen Hoffmann
- Dept. of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Dept. Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark
| | - Mikkel Mylius Rasmussen
- Dept. Neurosurgery, Cense-Spine, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 165 8200 Aarhus N, Aarhus, Denmark.,Dept. of Clinical Medicine, Aarhus University, Aarhus, Denmark
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24
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Ferrara M, Bertozzi G, Volonnino G, Di Fazio N, Frati P, Cipolloni L, La Russa R, Fineschi V. Glymphatic System a Window on TBI Pathophysiology: A Systematic Review. Int J Mol Sci 2022; 23:ijms23169138. [PMID: 36012401 PMCID: PMC9408940 DOI: 10.3390/ijms23169138] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Background: In recent years, the attention of the scientific world has focused on a clearance system of brain waste metabolites, called the glymphatic system, based on its similarity to the lymphatic system in peripheral tissue and the relevant role of the AQP4 glial channels and described for the first time in 2012. Consequently, numerous studies focused on its role in organ damage in cases of neuropathologies, including TBI. Methods: To evaluate the role that the glymphatic system has in the pathogenesis of TBI, on 23 March 2022, a systematic review of the literature according to PRISMA guidelines was carried out using the SCOPUS and Medline (via PubMed) databases, resulting in 12 articles after the selection process. Discussion and conclusion: The present review demonstrated that an alteration of AQP4 is associated with the accumulation of substances S100b, GFAP, and NSE, known markers of TBI in the forensic field. In addition, the alteration of the functionality of AQP4 favors edema, which, as already described, constitutes alterations of secondary brain injuries. Moreover, specific areas of the brain were demonstrated to be prone to alterations of the glymphatic pathway, suggesting their involvement in post-TBI damage. Therefore, further studies are mandatory. In this regard, a study protocol on cadavers is also proposed, based on the analyzed evidence.
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Affiliation(s)
- Michela Ferrara
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Giuseppe Bertozzi
- Department of Clinical and Experimental Medicine, Section of Legal Medicine, University of Foggia, 71122 Foggia, Italy
| | - Gianpietro Volonnino
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Nicola Di Fazio
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Paola Frati
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Luigi Cipolloni
- Department of Clinical and Experimental Medicine, Section of Legal Medicine, University of Foggia, 71122 Foggia, Italy
| | - Raffaele La Russa
- Department of Clinical and Experimental Medicine, Section of Legal Medicine, University of Foggia, 71122 Foggia, Italy
| | - Vittorio Fineschi
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, 00161 Rome, Italy
- Correspondence:
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25
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Bailey DM, Bain AR, Hoiland RL, Barak OF, Drvis I, Hirtz C, Lehmann S, Marchi N, Janigro D, MacLeod DB, Ainslie PN, Dujic Z. Hypoxemia increases blood-brain barrier permeability during extreme apnea in humans. J Cereb Blood Flow Metab 2022; 42:1120-1135. [PMID: 35061562 PMCID: PMC9121528 DOI: 10.1177/0271678x221075967] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Voluntary asphyxia imposed by static apnea challenges blood-brain barrier (BBB) integrity in humans through transient extremes of hypertension, hypoxemia and hypercapnia. In the present study, ten ultra-elite breath-hold divers performed two maximal dry apneas preceded by normoxic normoventilation (NX: severe hypoxemia and hypercapnia) and hyperoxic hyperventilation (HX: absence of hypoxemia with exacerbating hypercapnia) with measurements obtained before and immediately after apnea. Transcerebral exchange of NVU proteins (ELISA, Single Molecule Array) were calculated as the product of global cerebral blood flow (gCBF, duplex ultrasound) and radial arterial to internal jugular venous concentration gradients. Apnea duration increased from 5 m 6 s in NX to 15 m 59 s in HX (P = <0.001) resulting in marked elevations in gCBF and venous S100B, glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase-L1 and total tau (all P < 0.05 vs. baseline). This culminated in net cerebral output reflecting mildly increased BBB permeability and increased neuronal-gliovascular reactivity that was more pronounced in NX due to more severe systemic and intracranial hypertension (P < 0.05 vs. HX). These findings identify the hemodynamic stress to which the apneic brain is exposed, highlighting the critical contribution of hypoxemia and not just hypercapnia to BBB disruption.
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Affiliation(s)
- Damian M Bailey
- Neurovascular Research Laboratory, Faculty of Life Sciences and Education, 6654University of South Wales, University of South Wales, Glamorgan, UK
| | - Anthony R Bain
- Faculty of Human Kinetics, University of Windsor, Windsor, ON, Canada
| | - Ryan L Hoiland
- Department of Anaesthesiology, Pharmacology and Therapeutics, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.,Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Otto F Barak
- School of Medicine, University of Split, Split, Croatia.,Faculty of Medicine, University of Novi Sad, Serbia
| | - Ivan Drvis
- School of Kinesiology, University of Zagreb, Zagreb, Croatia
| | - Christophe Hirtz
- LBPC-PPC, University of Montpellier, Institute of Regenerative Medicine-Biotherapy IRMB, Centre Hospitalier Universitaire de Montpellier, INSERM, Montpellier, France
| | - Sylvain Lehmann
- LBPC-PPC, University of Montpellier, Institute of Regenerative Medicine-Biotherapy IRMB, Centre Hospitalier Universitaire de Montpellier, INSERM, Montpellier, France
| | - Nicola Marchi
- Institute of Functional Genomics, University of Montpellier, Montpellier, France
| | - Damir Janigro
- Department of Physiology, Case Western Reserve University, Cleveland, OH, USA.,FloTBI, Cleveland, OH, USA
| | - David B MacLeod
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Philip N Ainslie
- Neurovascular Research Laboratory, Faculty of Life Sciences and Education, 6654University of South Wales, University of South Wales, Glamorgan, UK.,Center for Heart Lung and Vascular Health, University of British Columbia, Kelowna, British Columbia, Canada
| | - Zeljko Dujic
- School of Medicine, University of Split, Split, Croatia
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26
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Girolamo F, Errede M, Bizzoca A, Virgintino D, Ribatti D. Central Nervous System Pericytes Contribute to Health and Disease. Cells 2022; 11:1707. [PMID: 35626743 PMCID: PMC9139243 DOI: 10.3390/cells11101707] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/16/2022] [Accepted: 05/18/2022] [Indexed: 12/11/2022] Open
Abstract
Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling could provide important insight into the function of the neurovascular unit (NVU), and into the injury-provoked responses that modify cell-cell interactions and crosstalk. Due to sharing the same basement membrane with endothelial cells, PCs have a crucial role in the control of endothelial, astrocyte, and oligodendrocyte precursor functions and hence blood-brain barrier stability. Both cerebrovascular and neurodegenerative diseases impair oxygen delivery and functionally impair the NVU. In this review, the role of PCs in central nervous system health and disease is discussed, considering their origin, multipotency, functions and also dysfunction, focusing on new possible avenues to modulate neuroprotection. Dysfunctional PC signalling could also be considered as a potential biomarker of NVU pathology, allowing us to individualize therapeutic interventions, monitor responses, or predict outcomes.
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Affiliation(s)
- Francesco Girolamo
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari ‘Aldo Moro’, 70124 Bari, Italy; (M.E.); (D.V.); (D.R.)
| | - Mariella Errede
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari ‘Aldo Moro’, 70124 Bari, Italy; (M.E.); (D.V.); (D.R.)
| | - Antonella Bizzoca
- Physiology Unit, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
| | - Daniela Virgintino
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari ‘Aldo Moro’, 70124 Bari, Italy; (M.E.); (D.V.); (D.R.)
| | - Domenico Ribatti
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari ‘Aldo Moro’, 70124 Bari, Italy; (M.E.); (D.V.); (D.R.)
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27
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Barbu M, Jónsson K, Zetterberg H, Blennow K, Kolsrud O, Ricksten S, Dellgren G, Björk K, Jeppsson A. Serum biomarkers of brain injury after uncomplicated cardiac surgery: Secondary analysis from a randomized trial. Acta Anaesthesiol Scand 2022; 66:447-453. [PMID: 35118644 PMCID: PMC9302991 DOI: 10.1111/aas.14033] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/16/2021] [Accepted: 01/22/2022] [Indexed: 11/29/2022]
Abstract
Background Postoperative cognitive dysfunction is common after cardiac surgery. Postoperative measurements of brain injury biomarkers may identify brain damage and predict cognitive dysfunction. We describe the release patterns of five brain injury markers in serum and plasma after uncomplicated cardiac surgery. Methods Sixty‐one elective cardiac surgery patients were randomized to undergo surgery with either a dextran‐based prime or a crystalloid prime. Blood samples were taken immediately before surgery, and 2 and 24 h after surgery. Concentrations of the brain injury biomarkers S100B, glial fibrillary acidic protein (GFAP), tau, neurofilament light (NfL) and neuron‐specific enolase (NSE)) and the blood–brain barrier injury marker β‐trace protein were analyzed. Concentrations of brain injury biomarkers were correlated to patients’ age, operation time, and degree of hemolysis. Results No significant difference in brain injury biomarkers was observed between the prime groups. All brain injury biomarkers increased significantly after surgery (tau +456% (25th–75th percentile 327%−702%), NfL +57% (28%−87%), S100B +1145% (783%−2158%), GFAP +17% (−3%−43%), NSE +168% (106%−228%), while β‐trace protein was reduced (−11% (−17−3%). Tau, S100B, and NSE peaked at 2h, NfL and GFAP at 24 h. Postoperative concentrations of brain injury markers correlated to age, operation time, and/or hemolysis. Conclusion Uncomplicated cardiac surgery with cardiopulmonary bypass is associated with an increase in serum/plasma levels of all the studied injury markers, without signs of blood–brain barrier injury. The biomarkers differ markedly in their levels of release and time course. Further investigations are required to study associations between perioperative release of biomarkers, postoperative cognitive function and clinical outcome.
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Affiliation(s)
- Mikael Barbu
- Department of Molecular and Clinical Medicine Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Department of Cardiology Blekinge Hospital Karlskrona Sweden
| | - Kristján Jónsson
- Department of Cardiothoracic Surgery Sahlgrenska University Hospital Gothenburg Sweden
| | - Henrik Zetterberg
- Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden
- Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy University of Gothenburg Mölndal Sweden
- Department of Neurodegenerative Disease UCL Institute of Neurology London UK
- UK Dementia Research Institute at UCL London UK
| | - Kaj Blennow
- Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden
- Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy University of Gothenburg Mölndal Sweden
| | - Oscar Kolsrud
- Department of Cardiothoracic Surgery Sahlgrenska University Hospital Gothenburg Sweden
| | - Sven‐Erik Ricksten
- Department of Cardiothoracic Anesthesia and Intensive Care Sahlgrenska University Hospital Gothenburg Sweden
- Department of Anesthesiology and Intensive Care Institute of Clinical Sciences University of Gothenburg Gothenburg Sweden
| | - Göran Dellgren
- Department of Molecular and Clinical Medicine Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Department of Cardiothoracic Surgery Sahlgrenska University Hospital Gothenburg Sweden
| | - Kerstin Björk
- Department of Cardiothoracic Surgery Sahlgrenska University Hospital Gothenburg Sweden
| | - Anders Jeppsson
- Department of Molecular and Clinical Medicine Institute of Medicine Sahlgrenska Academy University of Gothenburg Gothenburg Sweden
- Department of Cardiothoracic Surgery Sahlgrenska University Hospital Gothenburg Sweden
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28
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Taylor J, Parker M, Casey CP, Tanabe S, Kunkel D, Rivera C, Zetterberg H, Blennow K, Pearce RA, Lennertz RC, Sanders RD. Postoperative delirium and changes in the blood-brain barrier, neuroinflammation, and cerebrospinal fluid lactate: a prospective cohort study. Br J Anaesth 2022; 129:219-230. [PMID: 35144802 PMCID: PMC9465948 DOI: 10.1016/j.bja.2022.01.005] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/28/2021] [Accepted: 01/03/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Case-control studies have associated delirium with blood-brain barrier (BBB) permeability. However, this approach cannot determine whether delirium is attributable to high pre-existing permeability or to perioperative changes. We tested whether perioperative changes in cerebrospinal fluid/plasma albumin ratio (CPAR) and plasma S100B were associated with delirium severity. METHODS Participants were recruited to two prospective cohort studies of non-intracranial surgery (NCT01980511, NCT03124303, and NCT02926417). Delirium severity was assessed using the Delirium Rating Scale-98. Delirium incidence was diagnosed with the 3D-Confusion Assessment Method (3D-CAM) or CAM-ICU (CAM for the ICU). CSF samples from 25 patients and plasma from 78 patients were analysed for albumin and S100B. We tested associations between change in CPAR (n=11) and S100B (n=61) and delirium, blood loss, CSF interleukin-6 (IL-6), and CSF lactate. RESULTS The perioperative increase in CPAR and S100B correlated with delirium severity (CPAR ρ=0.78, P=0.01; S100B ρ=0.41, P<0.001), delirium incidence (CPAR P=0.012; S100B P<0.001) and CSF IL-6 (CPAR ρ=0.66 P=0.04; S100B ρ=0.75, P=0.025). Linear mixed-effect analysis also showed that decreased levels of S100B predicted recovery from delirium symptoms (P=0.001). Linear regression demonstrated that change in plasma S100B was independently associated with surgical risk, cardiovascular surgery, blood loss, and hypotension. Blood loss also correlated with CPAR (ρ=0.64, P=0.04), S100B (ρ=0.70, P<0.001), CSF lactate (R=0.81, P=0.01), and peak delirium severity (ρ=0.36, P=0.01). CONCLUSION Postoperative delirium is associated with a breakdown in the BBB. This increased permeability is dynamic and associated with a neuroinflammatory and lactate response. Strategies to mitigate blood loss may protect the BBB.
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Affiliation(s)
- Jennifer Taylor
- Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Anaesthetics, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, Australia
| | - Margaret Parker
- Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Cameron P Casey
- Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Sean Tanabe
- Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - David Kunkel
- Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Cameron Rivera
- Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
| | - Robert A Pearce
- Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Richard C Lennertz
- Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Robert D Sanders
- Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Anaesthetics, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, Australia.
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29
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Whitehouse DP, Vile AR, Adatia K, Herlekar R, Roy AS, Mondello S, Czeiter E, Amrein K, Büki A, Maas AIR, Menon DK, Newcombe VFJ. Blood Biomarkers and Structural Imaging Correlations Post-Traumatic Brain Injury: A Systematic Review. Neurosurgery 2022; 90:170-179. [PMID: 34995235 DOI: 10.1227/neu.0000000000001776] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 08/24/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Blood biomarkers are of increasing importance in the diagnosis and assessment of traumatic brain injury (TBI). However, the relationship between them and lesions seen on imaging remains unclear. OBJECTIVE To perform a systematic review of the relationship between blood biomarkers and intracranial lesion types, intracranial lesion injury patterns, volume/number of intracranial lesions, and imaging classification systems. METHODS We searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica dataBASE, and Cumulative Index to Nursing and Allied Health Literature from inception to May 2021, and the references of included studies were also screened. Heterogeneity in study design, biomarker types, imaging modalities, and analyses inhibited quantitative analysis, with a qualitative synthesis presented. RESULTS Fifty-nine papers were included assessing one or more biomarker to imaging comparisons per paper: 30 assessed imaging classifications or injury patterns, 28 assessed lesion type, and 11 assessed lesion volume or number. Biomarker concentrations were associated with the burden of brain injury, as assessed by increasing intracranial lesion volume, increasing numbers of traumatic intracranial lesions, and positive correlations with imaging classification scores. There were inconsistent findings associating different biomarkers with specific imaging phenotypes including diffuse axonal injury, cerebral edema, and intracranial hemorrhage. CONCLUSION Blood-based biomarker concentrations after TBI are consistently demonstrated to correlate burden of intracranial disease. The relation with specific injury types is unclear suggesting a lack of diagnostic specificity and/or is the result of the complex and heterogeneous nature of TBI.
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Affiliation(s)
- Daniel P Whitehouse
- Department of Medicine, University Division of Anaesthesia, University of Cambridge, Cambridge, UK
| | | | - Krishma Adatia
- Department of Medicine, University Division of Anaesthesia, University of Cambridge, Cambridge, UK
| | - Rahul Herlekar
- School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Akangsha Sur Roy
- School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Endre Czeiter
- Department of Neurosurgery, Medical School, University of Pécs, Pécs, Hungary
- Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- MTA-PTE Clinical Neuroscience MR Research Group, Pécs, Hungary
| | - Krisztina Amrein
- Department of Neurosurgery, Medical School, University of Pécs, Pécs, Hungary
- Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - András Büki
- Department of Neurosurgery, Medical School, University of Pécs, Pécs, Hungary
- Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Andrew I R Maas
- Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium
| | - David K Menon
- Department of Medicine, University Division of Anaesthesia, University of Cambridge, Cambridge, UK
| | - Virginia F J Newcombe
- Department of Medicine, University Division of Anaesthesia, University of Cambridge, Cambridge, UK
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30
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Kamińska J, Dymicka-Piekarska V, Chrzanowski R, Sawicki K, Milewska AJ, Zińczuk J, Tylicka M, Jadeszko M, Mariak Z, Kratz EM, Matowicka-Karna J, Kornhuber J, Lewczuk P, Koper-Lenkiewicz OM. IL-6 Quotient (The Ratio of Cerebrospinal Fluid IL-6 to Serum IL-6) as a Biomarker of an Unruptured Intracranial Aneurysm. J Inflamm Res 2021; 14:6103-6114. [PMID: 34848990 PMCID: PMC8627317 DOI: 10.2147/jir.s335618] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/31/2021] [Indexed: 11/23/2022] Open
Abstract
Background Studies conducted so far have focused mainly on the assessment of IL-6 levels in patients with ruptured brain aneurysms. Carrying out detailed studies in patients with un-ruptured brain aneurysms (UIA) would be extremely important, as it would answer the question of whether IL-6 plays also a role in primary aneurysm formation and growth. Methods IL-6, S100, NSE, and albumin concentrations in 67 UIA patients and 17 individuals without vascular lesions in the brain were tested using in vitro diagnostic immunoassays according to the manufacturers' instructions. IL-6 Quotient was calculated by dividing cerebrospinal fluid (CSF) IL-6 by serum IL-6. Results We showed that IL-6 Quotient was significantly higher in UIA patients (1.78) compared to the control group (0.87; p<0.001). Multivariate logistic regression analysis demonstrated that a growth in IL-6 Quotient increases the probability of UIA diagnosis. In UIA patients CSF IL-6 concentration was significantly higher (4.55 pg/ml) compared to the serum concentration (2.39 pg/ml; p<0.001). In both the study and control group, the blood-brain barrier was intact, thus the CSF-blood gradient of the IL-6 concentration in UIA patients was likely to be the expression of local synthesis of the cytokine within the central nervous system. Patients with multiple brain aneurysms had significantly higher CSF IL-6 levels (5.08 pg/ml) compared to individuals with a single aneurysm (4.14 pg/ml; p=0.0227). Conclusion This totality of the may suggest IL-6 as a biomarker for UIA formation; however, further studies are needed to unequivocally confirm clinical application of IL-6 concentration evaluation.
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Affiliation(s)
- Joanna Kamińska
- Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Białystok, 15-269, Poland
| | - Violetta Dymicka-Piekarska
- Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Białystok, 15-269, Poland
| | - Robert Chrzanowski
- Department of Neurosurgery, Clinical Hospital of the Medical University of Białystok, Białystok, 15-276, Poland
| | - Karol Sawicki
- Department of Neurosurgery, Clinical Hospital of the Medical University of Białystok, Białystok, 15-276, Poland
| | - Anna J Milewska
- Department of Statistics and Medical Informatics, Medical University of Białystok, Białystok, 15-295, Poland
| | - Justyna Zińczuk
- Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Białystok, 15-269, Poland
| | - Marzena Tylicka
- Department of Biophysics, Medical University of Białystok, Białystok, 15-089, Poland
| | - Marek Jadeszko
- Department of Neurosurgery, Clinical Hospital of the Medical University of Białystok, Białystok, 15-276, Poland
| | - Zenon Mariak
- Department of Neurosurgery, Clinical Hospital of the Medical University of Białystok, Białystok, 15-276, Poland
| | - Ewa M Kratz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wrocław Medical University, Wrocław, 50-556, Poland
| | - Joanna Matowicka-Karna
- Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Białystok, 15-269, Poland
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, 91054, Germany
| | - Piotr Lewczuk
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, 91054, Germany.,Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, 15-269, Poland
| | - Olga M Koper-Lenkiewicz
- Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Białystok, 15-269, Poland
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Li Z, Zhang J, Halbgebauer S, Chandrasekar A, Rehman R, Ludolph A, Boeckers T, Huber-Lang M, Otto M, Roselli F, Heuvel FO. Differential effect of ethanol intoxication on peripheral markers of cerebral injury in murine blunt traumatic brain injury. BURNS & TRAUMA 2021; 9:tkab027. [PMID: 34604393 PMCID: PMC8484207 DOI: 10.1093/burnst/tkab027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 05/28/2021] [Indexed: 11/29/2022]
Abstract
Background Blood-based biomarkers have proven to be a reliable measure of the severity and outcome of traumatic brain injury (TBI) in both murine models and patients. In particular, neuron-specific enolase (NSE), neurofilament light (NFL) and S100 beta (S100B) have been investigated in the clinical setting post-injury. Ethanol intoxication (EI) remains a significant comorbidity in TBI, with 30–40% of patients having a positive blood alcohol concentration post-TBI. The effect of ethanol on blood-based biomarkers for the prognosis and diagnosis of TBI remains unclear. In this study, we investigated the effect of EI on NSE, NFL and S100B and their correlation with blood–brain barrier integrity in a murine model of TBI. Methods We used ultra-sensitive single-molecule array technology and enzyme-linked immunosorbent assay methods to measure NFL, NSE, S100B and claudin-5 concentrations in plasma 3 hours post-TBI. Results We showed that NFL, NSE and S100B were increased at 3 hours post-TBI. Interestingly, ethanol blood concentrations showed an inverse correlation with NSE but not with NFL or S100B. Claudin-5 levels were increased post-injury but no difference was detected compared to ethanol pretreatment. The increase in claudin-5 post-TBI was correlated with NFL but not with NSE or S100B. Conclusions Ethanol induces an effect on biomarker release in the bloodstream that is different from TBI not influenced by alcohol. This could be the basis of investigations into humans.
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Affiliation(s)
- Zhenghui Li
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Jin Zhang
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Steffen Halbgebauer
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Akila Chandrasekar
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Rida Rehman
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Albert Ludolph
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Tobias Boeckers
- German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, University Hospital, ZBMF - Helmhotzstrasse 8/1, 89081 Ulm, Germany
| | - Markus Otto
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Francesco Roselli
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Florian Olde Heuvel
- Department of Neurology, Ulm University, ZBMF - Helmholtzstrasse 8/1, 89081 Ulm, Germany
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McDonald SJ, Shultz SR, Agoston DV. The Known Unknowns: An Overview of the State of Blood-Based Protein Biomarkers of Mild Traumatic Brain Injury. J Neurotrauma 2021; 38:2652-2666. [PMID: 33906422 DOI: 10.1089/neu.2021.0011] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Blood-based protein biomarkers have revolutionized several fields of medicine by enabling molecular level diagnosis, as well as monitoring disease progression and treatment efficacy. Traumatic brain injury (TBI) so far has benefitted only moderately from using protein biomarkers to improve injury outcome. Because of its complexity and dynamic nature, TBI, especially its most prevalent mild form (mild TBI; mTBI), presents unique challenges toward protein biomarker discovery and validation given that blood is frequently obtained and processed outside of the clinical laboratory (e.g., athletic fields, battlefield) under variable conditions. As it stands, the field of mTBI blood biomarkers faces a number of outstanding questions. Do elevated blood levels of currently used biomarkers-ubiquitin carboxy-terminal hydrolase L1, glial fibrillary acidic protein, neurofilament light chain, and tau/p-tau-truly mirror the extent of parenchymal damage? Do these different proteins represent distinct injury mechanisms? Is the blood-brain barrier a "brick wall"? What is the relationship between intra- versus extracranial values? Does prolonged elevation of blood levels reflect de novo release or extended protein half-lives? Does biological sex affect the pathobiological responses after mTBI and thus blood levels of protein biomarkers? At the practical level, it is unknown how pre-analytical variables-sample collection, preparation, handling, and stability-affect the quality and reliability of biomarker data. The ever-increasing sensitivity of assay systems and lack of quality control of samples, combined with the almost complete reliance on antibody-based assay platforms, represent important unsolved issues given that false-negative results can lead to false clinical decision making and adverse outcomes. This article serves as a commentary on the state of mTBI biomarkers and the landscape of significant challenges. We highlight and discusses several biological and methodological "known unknowns" and close with some practical recommendations.
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Affiliation(s)
- Stuart J McDonald
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Bundoora, Victoria, Australia
| | - Sandy R Shultz
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia
| | - Denes V Agoston
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
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Roberts DJ, Hall RI, Wang Y, Julien LC, Wood J, Goralski KB. S100B as a biomarker of blood-brain barrier disruption after thoracoabdominal aortic aneurysm repair: a secondary analysis from a prospective cohort study. Can J Anaesth 2021; 68:1756-1768. [PMID: 34570352 DOI: 10.1007/s12630-021-02110-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 08/05/2021] [Accepted: 08/08/2021] [Indexed: 11/26/2022] Open
Abstract
PURPOSE The objective of this study was to determine whether the magnitude of the peripheral inflammatory response to cardiovascular surgery is associated with increases in blood-brain barrier (BBB) permeability as reflected by changes in cerebrospinal fluid (CSF)/plasma S100B concentrations. METHODS We conducted a secondary analysis from a prospective cohort study of 35 patients undergoing elective thoracoabdominal aortic aneurysm repair with (n = 17) or without (n = 18) cardiopulmonary bypass (CPB). Plasma and CSF S100B, interleukin-6 (IL-6), and albumin concentrations were measured at baseline (C0) and serially for up to five days. RESULTS Following CPB, the median [interquartile range] plasma S100B concentration increased from 58 [32-88] pg·mL-1 at C0 to a maximum concentration (Cmax) of 1,131 [655-1,875] pg·mL-1 over a median time (tmax) of 6.3 [5.9-7.0] hr. In the non-CPB group, the median plasma S100B increased to a lesser extent. There was a delayed increase in CSF S100B to a median Cmax of 436 [406-922] pg·mL-1 in the CPB group at a tmax of 23.7 [18.5-40.2] hr. In the non-CPB group, the CSF concentrations were similar at all time points. In the CPB group, we did not detect significant correlations between plasma and CSF S100B with plasma IL-6 [r = 0.52 (95% confidence interval [CI], -0.061 to 0.84)] and CSF IL-6 [r = 0.53 (95% CI, -0.073 to 0.85)] concentrations, respectively. Correlations of plasma or CSF S100B levels with BBB permeability were not significant. CONCLUSION The lack of parallel increases in plasma and CSF S100B following CPB indicates that S100B may not be a reliable biomarker for BBB disruption after thoracoabdominal aortic aneurysm repair employing CPB. TRIAL REGISTRATION www.clinicaltrials.gov (NCT00878371); registered 7 April 2009.
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Affiliation(s)
- Derek J Roberts
- Division of Vascular and Endovascular Surgery, Department of Surgery, University of Ottawa, Ottawa, ON, Canada
- The Clinical Epidemiology Program, The Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- The O'Brien Institute for Public Health, University of Calgary, Calgary, AB, Canada
| | - Richard I Hall
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
- Department of Critical Care Medicine, Central Zone, Nova Scotia Health Authority, Halifax, NS, Canada
- Department of Anesthesia, Pain Management, and Perioperative Medicine, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Yan Wang
- College of Pharmacy, Faculty of Health, Dalhousie University, Halifax, NS, B3H 4R2, Canada
| | - Lisa C Julien
- Department of Critical Care Medicine, Central Zone, Nova Scotia Health Authority, Halifax, NS, Canada
| | - Jeremy Wood
- Divisions of Cardiac and Vascular Surgery, Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Kerry B Goralski
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
- College of Pharmacy, Faculty of Health, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
- Department of Pediatrics, Faculty of Medicine, Dalhousie University and IWK Health Centre, Halifax, NS, Canada.
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Hier DB, Obafemi-Ajayi T, Thimgan MS, Olbricht GR, Azizi S, Allen B, Hadi BA, Wunsch DC. Blood biomarkers for mild traumatic brain injury: a selective review of unresolved issues. Biomark Res 2021; 9:70. [PMID: 34530937 PMCID: PMC8447604 DOI: 10.1186/s40364-021-00325-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/26/2021] [Indexed: 01/03/2023] Open
Abstract
Background The use of blood biomarkers after mild traumatic brain injury (mTBI) has been widely studied. We have identified eight unresolved issues related to the use of five commonly investigated blood biomarkers: neurofilament light chain, ubiquitin carboxy-terminal hydrolase-L1, tau, S100B, and glial acidic fibrillary protein. We conducted a focused literature review of unresolved issues in three areas: mode of entry into and exit from the blood, kinetics of blood biomarkers in the blood, and predictive capacity of the blood biomarkers after mTBI. Findings Although a disruption of the blood brain barrier has been demonstrated in mild and severe traumatic brain injury, biomarkers can enter the blood through pathways that do not require a breach in this barrier. A definitive accounting for the pathways that biomarkers follow from the brain to the blood after mTBI has not been performed. Although preliminary investigations of blood biomarkers kinetics after TBI are available, our current knowledge is incomplete and definitive studies are needed. Optimal sampling times for biomarkers after mTBI have not been established. Kinetic models of blood biomarkers can be informative, but more precise estimates of kinetic parameters are needed. Confounding factors for blood biomarker levels have been identified, but corrections for these factors are not routinely made. Little evidence has emerged to date to suggest that blood biomarker levels correlate with clinical measures of mTBI severity. The significance of elevated biomarker levels thirty or more days following mTBI is uncertain. Blood biomarkers have shown a modest but not definitive ability to distinguish concussed from non-concussed subjects, to detect sub-concussive hits to the head, and to predict recovery from mTBI. Blood biomarkers have performed best at distinguishing CT scan positive from CT scan negative subjects after mTBI.
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Affiliation(s)
- Daniel B Hier
- Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, MO 65401, USA.
| | - Tayo Obafemi-Ajayi
- Cooperative Engineering Program, Missouri State University, Springfield, MO 65897, United States
| | - Matthew S Thimgan
- Department of Biological Sciences, Missouri University of Science and Technology, Rolla, MO 65409, United States
| | - Gayla R Olbricht
- Department of Mathematics and Statistics, Missouri University of Science and Technology, Rolla, MO 65409, United States
| | - Sima Azizi
- Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, MO 65401, USA
| | - Blaine Allen
- Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, MO 65401, USA
| | - Bassam A Hadi
- Department of Surgery, Mercy Hospital, St. Louis MO, Missouri, MO 63141, United States
| | - Donald C Wunsch
- Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, MO 65401, USA.,National Science Foundation, ECCS Division, Virginia, 22314, USA
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35
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Zeiler FA, Iturria-Medina Y, Thelin EP, Gomez A, Shankar JJ, Ko JH, Figley CR, Wright GEB, Anderson CM. Integrative Neuroinformatics for Precision Prognostication and Personalized Therapeutics in Moderate and Severe Traumatic Brain Injury. Front Neurol 2021; 12:729184. [PMID: 34557154 PMCID: PMC8452858 DOI: 10.3389/fneur.2021.729184] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/09/2021] [Indexed: 01/13/2023] Open
Abstract
Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) over the preceding decades, little impact on mortality and morbidity have been seen. This argues against the "one-treatment fits all" approach to such management strategies. With this, some preliminary advances in the area of personalized medicine in TBI care have displayed promising results. However, to continue transitioning toward individually-tailored care, we require integration of complex "-omics" data sets. The past few decades have seen dramatic increases in the volume of complex multi-modal data in moderate and severe TBI care. Such data includes serial high-fidelity multi-modal characterization of the cerebral physiome, serum/cerebrospinal fluid proteomics, admission genetic profiles, and serial advanced neuroimaging modalities. Integrating these complex and serially obtained data sets, with patient baseline demographics, treatment information and clinical outcomes over time, can be a daunting task for the treating clinician. Within this review, we highlight the current status of such multi-modal omics data sets in moderate/severe TBI, current limitations to the utilization of such data, and a potential path forward through employing integrative neuroinformatic approaches, which are applied in other neuropathologies. Such advances are positioned to facilitate the transition to precision prognostication and inform a top-down approach to the development of personalized therapeutics in moderate/severe TBI.
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Affiliation(s)
- Frederick A. Zeiler
- Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, MB, Canada
- Centre on Aging, University of Manitoba, Winnipeg, MB, Canada
- Division of Anaesthesia, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom
| | - Yasser Iturria-Medina
- Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
- McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
- Ludmer Centre for Neuroinformatics and Mental Health, Montreal, QC, Canada
| | - Eric P. Thelin
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Alwyn Gomez
- Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Jai J. Shankar
- Department of Radiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Ji Hyun Ko
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Winnipeg, MB, Canada
| | - Chase R. Figley
- Department of Radiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Winnipeg, MB, Canada
| | - Galen E. B. Wright
- Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Winnipeg, MB, Canada
- Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Chris M. Anderson
- Neuroscience Research Program, Kleysen Institute for Advanced Medicine, Winnipeg, MB, Canada
- Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
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36
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Tobieson L, Zetterberg H, Blennow K, Marklund N. Extracellular fluid, cerebrospinal fluid and plasma biomarkers of axonal and neuronal injury following intracerebral hemorrhage. Sci Rep 2021; 11:16950. [PMID: 34417515 PMCID: PMC8379247 DOI: 10.1038/s41598-021-96364-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/03/2021] [Indexed: 12/26/2022] Open
Abstract
Spontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.
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Affiliation(s)
- Lovisa Tobieson
- Department of Neurosurgery in Linköping, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.,Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.,UK Dementia Research Institute at UCL, London, UK
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Niklas Marklund
- Department of Neurosurgery in Linköping, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.,Department of Clinical Sciences Lund, Neurosurgery, Skåne University Hospital, Lund University, Lund, Sweden
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37
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Zwirner J, Anders S, Bohnert S, Burkhardt R, Da Broi U, Hammer N, Pohlers D, Tse R, Ondruschka B. Screening for Fatal Traumatic Brain Injuries in Cerebrospinal Fluid Using Blood-Validated CK and CK-MB Immunoassays. Biomolecules 2021; 11:1061. [PMID: 34356685 PMCID: PMC8301791 DOI: 10.3390/biom11071061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/05/2021] [Accepted: 07/17/2021] [Indexed: 12/13/2022] Open
Abstract
A single, specific, sensitive biochemical biomarker that can reliably diagnose a traumatic brain injury (TBI) has not yet been found, but combining different biomarkers would be the most promising approach in clinical and postmortem settings. In addition, identifying new biomarkers and developing laboratory tests can be time-consuming and economically challenging. As such, it would be efficient to use established clinical diagnostic assays for postmortem biochemistry. In this study, postmortem cerebrospinal fluid samples from 45 lethal TBI cases and 47 controls were analyzed using commercially available blood-validated assays for creatine kinase (CK) activity and its heart-type isoenzyme (CK-MB). TBI cases with a survival time of up to two hours showed an increase in both CK and CK-MB with moderate (CK-MB: AUC = 0.788, p < 0.001) to high (CK: AUC = 0.811, p < 0.001) diagnostic accuracy. This reflected the excessive increase of the brain-type CK isoenzyme (CK-BB) following a TBI. The results provide evidence that CK immunoassays can be used as an adjunct quantitative test aid in diagnosing acute TBI-related fatalities.
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Affiliation(s)
- Johann Zwirner
- Department of Anatomy, University of Otago, Dunedin 9016, New Zealand
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany;
- Institute of Legal Medicine, University of Leipzig, 04103 Leipzig, Germany
| | - Sven Anders
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany;
| | - Simone Bohnert
- Institute of Forensic Medicine, University of Wuerzburg, 97078 Wuerzburg, Germany;
| | - Ralph Burkhardt
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, 93053 Regensburg, Germany;
| | - Ugo Da Broi
- Department of Medicine, Forensic Medicine, University of Udine, 33100 Udine, Italy;
| | - Niels Hammer
- Institute of Macroscopic and Clinical Anatomy, University of Graz, 8010 Graz, Austria;
- Department of Trauma, Orthopedic and Plastic Surgery, University Hospital of Leipzig, 04103 Leipzig, Germany
- Fraunhofer Institute for Machine Tools and Forming Technology, 09126 Dresden, Germany
| | - Dirk Pohlers
- Center of Diagnostics, Klinikum Chemnitz, 09116 Chemnitz, Germany;
| | - Rexson Tse
- Department of Forensic Pathology, LabPLUS, Auckland City Hospital, Auckland 1023, New Zealand;
| | - Benjamin Ondruschka
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, 22529 Hamburg, Germany;
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38
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Azizi S, Hier DB, Allen B, Obafemi-Ajayi T, Olbricht GR, Thimgan MS, Wunsch DC. A Kinetic Model for Blood Biomarker Levels After Mild Traumatic Brain Injury. Front Neurol 2021; 12:668606. [PMID: 34295300 PMCID: PMC8289906 DOI: 10.3389/fneur.2021.668606] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 06/09/2021] [Indexed: 01/23/2023] Open
Abstract
Traumatic brain injury (TBI) imposes a significant economic and social burden. The diagnosis and prognosis of mild TBI, also called concussion, is challenging. Concussions are common among contact sport athletes. After a blow to the head, it is often difficult to determine who has had a concussion, who should be withheld from play, if a concussed athlete is ready to return to the field, and which concussed athlete will develop a post-concussion syndrome. Biomarkers can be detected in the cerebrospinal fluid and blood after traumatic brain injury and their levels may have prognostic value. Despite significant investigation, questions remain as to the trajectories of blood biomarker levels over time after mild TBI. Modeling the kinetic behavior of these biomarkers could be informative. We propose a one-compartment kinetic model for S100B, UCH-L1, NF-L, GFAP, and tau biomarker levels after mild TBI based on accepted pharmacokinetic models for oral drug absorption. We approximated model parameters using previously published studies. Since parameter estimates were approximate, we did uncertainty and sensitivity analyses. Using estimated kinetic parameters for each biomarker, we applied the model to an available post-concussion biomarker dataset of UCH-L1, GFAP, tau, and NF-L biomarkers levels. We have demonstrated the feasibility of modeling blood biomarker levels after mild TBI with a one compartment kinetic model. More work is needed to better establish model parameters and to understand the implications of the model for diagnostic use of these blood biomarkers for mild TBI.
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Affiliation(s)
- Sima Azizi
- Applied Computational Intelligence Laboratory, Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, MO, United States
| | - Daniel B Hier
- Applied Computational Intelligence Laboratory, Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, MO, United States
| | - Blaine Allen
- Applied Computational Intelligence Laboratory, Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, MO, United States
| | - Tayo Obafemi-Ajayi
- Engineering Program, Missouri State University, Springfield, MO, United States
| | - Gayla R Olbricht
- Department of Mathematics and Statistics, Missouri University of Science and Technology, Rolla, MO, United States
| | - Matthew S Thimgan
- Department of Biological Sciences, Missouri University of Science and Technology, Rolla, MO, United States
| | - Donald C Wunsch
- Applied Computational Intelligence Laboratory, Department of Electrical and Computer Engineering, Missouri University of Science and Technology, Rolla, MO, United States.,ECCS Division, National Science Foundation, Alexandria, VA, United States
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39
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Li M, Ye M, Zhang G. Aberrant expression of miR-199a in newborns with hypoxic-ischemic encephalopathy and its diagnostic and prognostic significance when combined with S100B and NSE. Acta Neurol Belg 2021; 121:707-714. [PMID: 32533551 DOI: 10.1007/s13760-020-01408-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 06/08/2020] [Indexed: 01/20/2023]
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is a disorder mainly due to asphyxia during the perinatal period, and late diagnosis leads to high mortality. In this study, the expression of microRNA-199a (miR-199a) in HIE newborns was investigated, as well as its clinical significance in HIE diagnosis and prognosis. Circulating levels of S100B and NSE in HIE newborns were measured using enzyme-linked immunosorbent assay, and the expression of miR-199a was analyzed using quantitative real-time PCR. The diagnostic value of miR-199a, S100B and NSE was evaluated using the receiver operating characteristic (ROC) analysis, and their prognostic value was assessed by the evaluation of Gesell intellectual development of the HIE newborns. HIE newborns possessed significantly increased levels of S100B and NSE and decreased miR-199a (all P < 0.01). The Neonatal Behavioral Neurological Assessment (NBNA) score of HIE newborns was negatively correlated with S100B and NSE, while was positively correlated miR-199a. The ROC analysis results showed the diagnostic value of serum miR-199a, and the combined detection of miR-199a, S100B and NSE could obtained the highest diagnostic accuracy in HIE newborns. miR-199a expression was lowest in newborns with severe HIE, and it had diagnostic potential to distinguish HIE cases with different severity. Regarding the prognosis of neonatal HIE, the correlation of miR-199a, S100B, NSE with Gesell intellectual development was found in HIE newborns. The decreased miR-199a in HIE newborns serves as a potential diagnostic biomarker and may help to improve the diagnostic and prognostic value of S100B and NSE in neonatal HIE.
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Affiliation(s)
- Min Li
- Department of Neonatology, Women and Children's Health Care Hospital of Linyi, Linyi, 276001, Shandong, China
| | - Mei Ye
- Department of Neonatology, Women and Children's Health Care Hospital of Linyi, Linyi, 276001, Shandong, China
| | - Guangyun Zhang
- Department of Pediatrics, Women and Children's Health Care Hospital of Linyi, No.1, Qinghe South Road, Linyi, 276001, Shandong, China.
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40
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Kubis-Kubiak A, Wiatrak B, Piwowar A. The Impact of High Glucose or Insulin Exposure on S100B Protein Levels, Oxidative and Nitrosative Stress and DNA Damage in Neuron-Like Cells. Int J Mol Sci 2021; 22:ijms22115526. [PMID: 34073816 PMCID: PMC8197274 DOI: 10.3390/ijms22115526] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 12/25/2022] Open
Abstract
Alzheimer’s disease (AD) is attracting considerable interest due to its increasing number of cases as a consequence of the aging of the global population. The mainstream concept of AD neuropathology based on pathological changes of amyloid β metabolism and the formation of neurofibrillary tangles is under criticism due to the failure of Aβ-targeting drug trials. Recent findings have shown that AD is a highly complex disease involving a broad range of clinical manifestations as well as cellular and biochemical disturbances. The past decade has seen a renewed importance of metabolic disturbances in disease-relevant early pathology with challenging areas in establishing the role of local micro-fluctuations in glucose concentrations and the impact of insulin on neuronal function. The role of the S100 protein family in this interplay remains unclear and is the aim of this research. Intracellularly the S100B protein has a protective effect on neurons against the toxic effects of glutamate and stimulates neurites outgrowth and neuronal survival. At high concentrations, it can induce apoptosis. The aim of our study was to extend current knowledge of the possible impact of hyper-glycemia and -insulinemia directly on neuronal S100B secretion and comparison to oxidative stress markers such as ROS, NO and DBSs levels. In this paper, we have shown that S100B secretion decreases in neurons cultured in a high-glucose or high-insulin medium, while levels in cell lysates are increased with statistical significance. Our findings demonstrate the strong toxic impact of energetic disturbances on neuronal metabolism and the potential neuroprotective role of S100B protein.
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Affiliation(s)
- Adriana Kubis-Kubiak
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland;
- Correspondence:
| | - Benita Wiatrak
- Department of Pharmacology, Faculty of Medicine, Wroclaw Medical University, Mikulicza-Radeckiego 2, 50-345 Wroclaw, Poland;
| | - Agnieszka Piwowar
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland;
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41
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Amoo M, O'Halloran PJ, Henry J, Husien MB, Brennan P, Campbell M, Caird J, Curley GF. Permeability of the Blood-Brain Barrier after Traumatic Brain Injury; Radiological Considerations. J Neurotrauma 2021; 39:20-34. [PMID: 33632026 DOI: 10.1089/neu.2020.7545] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability, especially in young persons, and constitutes a major socioeconomic burden worldwide. It is regarded as the leading cause of mortality and morbidity in previously healthy young persons. Most of the mechanisms underpinning the development of secondary brain injury are consequences of disruption of the complex relationship between the cells and proteins constituting the neurovascular unit or a direct result of loss of integrity of the tight junctions (TJ) in the blood-brain barrier (BBB). A number of changes have been described in the BBB after TBI, including loss of TJ proteins, pericyte loss and migration, and altered expressions of water channel proteins at astrocyte end-feet processes. There is a growing research interest in identifying optimal biological and radiological biomarkers of severity of BBB dysfunction and its effects on outcomes after TBI. This review explores the microscopic changes occurring at the neurovascular unit, after TBI, and current radiological adjuncts for its evaluation in pre-clinical and clinical practice.
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Affiliation(s)
- Michael Amoo
- National Centre for Neurosurgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.,Royal College of Surgeons in Ireland, Dublin, Ireland.,Beacon Academy, Beacon Hospital, Sandyford, Dublin, Ireland
| | - Philip J O'Halloran
- Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Neurosurgery, Royal London Hospital, Whitechapel, London, United Kingdom
| | - Jack Henry
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Mohammed Ben Husien
- National Centre for Neurosurgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.,Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Paul Brennan
- Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Radiology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | | | - John Caird
- National Centre for Neurosurgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Gerard F Curley
- Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Anaesthesia and Critical Care, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
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42
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Lindblad C, Pin E, Just D, Al Nimer F, Nilsson P, Bellander BM, Svensson M, Piehl F, Thelin EP. Fluid proteomics of CSF and serum reveal important neuroinflammatory proteins in blood-brain barrier disruption and outcome prediction following severe traumatic brain injury: a prospective, observational study. Crit Care 2021; 25:103. [PMID: 33712077 PMCID: PMC7955664 DOI: 10.1186/s13054-021-03503-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 02/10/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Severe traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls. METHODS We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6-12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (QA), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort. RESULTS TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with QA, among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained ~ 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, ΔR2 = 7.4%) and complement factor B in serum (p = 0.003, ΔR2 = 9.2%) were independent outcome predictors also following step-down modelling. CONCLUSIONS This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.
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Affiliation(s)
- Caroline Lindblad
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
| | - Elisa Pin
- Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH-Royal Institute of Technology, Stockholm, Sweden
| | - David Just
- Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH-Royal Institute of Technology, Stockholm, Sweden
| | - Faiez Al Nimer
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden
| | - Peter Nilsson
- Division of Affinity Proteomics, Department of Protein Science, SciLifeLab, KTH-Royal Institute of Technology, Stockholm, Sweden
| | - Bo-Michael Bellander
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
| | - Mikael Svensson
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
| | - Fredrik Piehl
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden
| | - Eric Peter Thelin
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
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43
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Balança B, Desmurs L, Grelier J, Perret-Liaudet A, Lukaszewicz AC. DAMPs and RAGE Pathophysiology at the Acute Phase of Brain Injury: An Overview. Int J Mol Sci 2021; 22:ijms22052439. [PMID: 33670976 PMCID: PMC7957733 DOI: 10.3390/ijms22052439] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/17/2021] [Accepted: 02/23/2021] [Indexed: 12/14/2022] Open
Abstract
Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for “DAMPs” or “RAGE” or “S100B” and “traumatic brain injury” or “subarachnoid hemorrhage” or “stroke”. We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives
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Affiliation(s)
- Baptiste Balança
- Department of Neurological Anesthesiology and Intensive Care Medicine, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, 69500 Bron, France;
- Team TIGER, Lyon Neuroscience Research Centre, Inserm U1028, CNRS UMR 5292, 69500 Bron, France
- Correspondence: ; Tel.: +33-6-2391-0594
| | - Laurent Desmurs
- Clinical Chemistry and Molecular Biology Laboratory, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, 69500 Bron, France; (L.D.); (A.P.-L.)
| | - Jérémy Grelier
- Department of Neurological Anesthesiology and Intensive Care Medicine, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, 69500 Bron, France;
| | - Armand Perret-Liaudet
- Clinical Chemistry and Molecular Biology Laboratory, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, 69500 Bron, France; (L.D.); (A.P.-L.)
- Team BIORAN, Lyon Neuroscience Research Centre, Inserm U1028, CNRS UMR 5292, 69500 Bron, France
| | - Anne-Claire Lukaszewicz
- Department of Neurological Anesthesiology and Intensive Care Medicine, Hospices Civils de Lyon, Hôpital Edouard Herriot, 69003 Lyon, France;
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Janigro D, Bailey DM, Lehmann S, Badaut J, O'Flynn R, Hirtz C, Marchi N. Peripheral Blood and Salivary Biomarkers of Blood-Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts. Front Neurol 2021; 11:577312. [PMID: 33613412 PMCID: PMC7890078 DOI: 10.3389/fneur.2020.577312] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022] Open
Abstract
Within the neurovascular unit (NVU), the blood–brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.
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Affiliation(s)
- Damir Janigro
- Department of Physiology Case Western Reserve University, Cleveland, OH, United States.,FloTBI Inc., Cleveland, OH, United States
| | - Damian M Bailey
- Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Wales, United Kingdom
| | - Sylvain Lehmann
- IRMB, INM, UFR Odontology, University Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Jerome Badaut
- Brain Molecular Imaging Lab, CNRS UMR 5287, INCIA, University of Bordeaux, Bordeaux, France
| | - Robin O'Flynn
- IRMB, INM, UFR Odontology, University Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Christophe Hirtz
- IRMB, INM, UFR Odontology, University Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Nicola Marchi
- Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional Genomics (UMR 5203 CNRS-U 1191 INSERM, University of Montpellier), Montpellier, France
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DeKosky ST, Kochanek PM, Valadka AB, Clark RS, Chou SHY, Au AK, Horvat C, Jha RM, Mannix R, Wisniewski SR, Wintermark M, Rowell SE, Welch RD, Lewis L, House S, Tanzi RE, Smith DR, Vittor AY, Denslow ND, Davis MD, Glushakova OY, Hayes RL. Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients. J Neurotrauma 2021; 38:1-43. [PMID: 33115334 PMCID: PMC7757533 DOI: 10.1089/neu.2020.7332] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus attacks multiple organs of coronavirus disease 2019 (COVID-19) patients, including the brain. There are worldwide descriptions of neurological deficits in COVID-19 patients. Central nervous system (CNS) symptoms can be present early in the course of the disease. As many as 55% of hospitalized COVID-19 patients have been reported to have neurological disturbances three months after infection by SARS-CoV-2. The mutability of the SARS-COV-2 virus and its potential to directly affect the CNS highlight the urgency of developing technology to diagnose, manage, and treat brain injury in COVID-19 patients. The pathobiology of CNS infection by SARS-CoV-2 and the associated neurological sequelae of this infection remain poorly understood. In this review, we outline the rationale for the use of blood biomarkers (BBs) for diagnosis of brain injury in COVID-19 patients, the research needed to incorporate their use into clinical practice, and the improvements in patient management and outcomes that can result. BBs of brain injury could potentially provide tools for detection of brain injury in COVID-19 patients. Elevations of BBs have been reported in cerebrospinal fluid (CSF) and blood of COVID-19 patients. BB proteins have been analyzed in CSF to detect CNS involvement in patients with infectious diseases, including human immunodeficiency virus and tuberculous meningitis. BBs are approved by the U.S. Food and Drug Administration for diagnosis of mild versus moderate traumatic brain injury and have identified brain injury after stroke, cardiac arrest, hypoxia, and epilepsy. BBs, integrated with other diagnostic tools, could enhance understanding of viral mechanisms of brain injury, predict severity of neurological deficits, guide triage of patients and assignment to appropriate medical pathways, and assess efficacy of therapeutic interventions in COVID-19 patients.
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Affiliation(s)
- Steven T. DeKosky
- McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Patrick M. Kochanek
- Department of Critical Care Medicine, Department of Anesthesiology, Pediatrics, Bioengineering, and Clinical and Translational Science, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alex B. Valadka
- Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Robert S.B. Clark
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Sherry H.-Y. Chou
- Department of Critical Care Medicine, Neurology, and Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Alicia K. Au
- University of Pittsburgh, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Christopher Horvat
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Division of Pediatric Critical Care, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ruchira M. Jha
- Departments of Critical Care Medicine, Neurology, Neurological Surgery, Clinical and Translational Science Institute, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Rebekah Mannix
- Department of Pediatrics and Emergency Medicine, Harvard Medical School, Department of Medicine, Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | | | - Max Wintermark
- Department of Neuroradiology, Stanford University, Stanford, California, USA
| | - Susan E. Rowell
- Duke University School of Medicine, Durham, North Carolina, USA
| | - Robert D. Welch
- Department of Emergency Medicine, Wayne State University School of Medicine, Detroit Receiving Hospital/University Health Center, Detroit, Michigan, USA
| | - Lawrence Lewis
- Department of Emergency Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Stacey House
- Department of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Rudolph E. Tanzi
- Genetics and Aging Research Unit, Massachusetts General Hospital, McCance Center for Brain Health, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Department of Neurology (Research), Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Charlestown, Massachusetts, USA
| | - Darci R. Smith
- Immunodiagnostics Department, Naval Medical Research Center, Biological Defense Research Directorate, Fort Detrick, Maryland, USA
| | - Amy Y. Vittor
- Division of Infectious Disease and Global Medicine, University of Florida, Emerging Pathogens Institute, Gainesville, Florida, USA
| | - Nancy D. Denslow
- Departments of Physiological Sciences and Biochemistry and Molecular Biology, University of Florida, Center for Environmental and Human Toxicology, Gainesville, Florida
| | - Michael D. Davis
- Department of Pediatrics, Wells Center for Pediatric Research/Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children at Indiana University, Indianapolis, Indiana, USA
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Li D, Zhang Y, Lu L, Zhang L, Ma J, Ji J, Li H, Chen G. Upregulation of Sec22b plays a neuroprotective role in a rat model of traumatic brain injury via inducing protective autophagy. Brain Res Bull 2020; 166:29-36. [PMID: 33186631 DOI: 10.1016/j.brainresbull.2020.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 11/03/2020] [Accepted: 11/06/2020] [Indexed: 11/16/2022]
Abstract
Cortical neuronal cell death following traumatic brain injury (TBI) evoked by the cortical impact is a significant factor that contributes to neurological deficits. In the current study, we harvested the injured area and perilesional area of the injured brain induced by TBI. We explored the functions of Sec22b, an apoptosis-promoting kinase, and a pivotal bridge builder of apoptotic signaling in the etiopathogenesis of an experimental rat model of TBI. We found that Sec22b was expressed in neurons in the injured cortical area, and the expression level significantly decreased after TBI, especially at 24 h. Administration of Sec22b overexpressed plasmid significantly ameliorated TBI-induced apoptosis, neurological deficits, and blood-brain barrier permeability, accompanied by the activation of autophagy. However, the administration of Sec22b knockdown resulted in the opposite eff ;ects. Altogether, these findings indicated that Sec22b plays a neuroprotective role after TBI, suggesting that Sec22b may be a potential therapeutic target for TBI. We speculated that this neuroprotective effect might be achieved by upregulating autophagy levels and required further studies to explore.
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Affiliation(s)
- Di Li
- Department of Neurosurgery and Translational Medicine Center, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Yan Zhang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lina Lu
- Department of Radiation Oncology, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Ling Zhang
- Department of Neurosurgery and Translational Medicine Center, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Jialing Ma
- Department of Anesthesia, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China
| | - Jiaxuan Ji
- Department of Neurosurgery, Zhangjiagang Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Suzhou, China.
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
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Huibregtse ME, Nowak MK, Kim JE, Kalbfell RM, Koppineni A, Ejima K, Kawata K. Does acute soccer heading cause an increase in plasma S100B? A randomized controlled trial. PLoS One 2020; 15:e0239507. [PMID: 33096545 PMCID: PMC7584162 DOI: 10.1371/journal.pone.0239507] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 09/08/2020] [Indexed: 12/14/2022] Open
Abstract
The purpose of this study was to test the effect of subconcussive head impacts on acute changes in plasma S100B. In this randomized controlled trial, 79 healthy adult soccer players were randomly assigned to either the heading (n = 41) or kicking-control groups (n = 38). The heading group executed 10 headers with soccer balls projected at a speed of 25 mph, whereas the kicking-control group performed 10 kicks. Plasma samples were obtained at pre-, 0h post-, 2h post- and 24h post-intervention and measured for S100B. The primary hypothesis was that there would be a significant group difference (group-by-time interaction) in plasma S100B at 2h post-intervention. Secondary hypotheses included (1) no significant group differences in plasma S100B concentrations at 0h post- and 24h post-intervention; (2) a significant within-group increase in S100B concentrations in the heading group at 2h post-intervention compared to pre-intervention; and (3) no significant within-group changes in plasma S100B in the kicking-control group. Data from 68 subjects were available for analysis (heading n = 37, kicking n = 31). There were no differences in S100B concentrations between heading and kicking groups over time, as evidenced by nonsignificant group-by-time interaction at 2h post-intervention (B = 2.20, 95%CI [-22.22, 26.63], p = 0.86) and at all the other time points (0h post: B = -11.05, 95%CI [-35.37, 13.28], p = 0.38; 24h post: B = 16.11, 95%CI [-8.29, 40.51], p = 0.20). Part of the secondary outcome, the heading group showed elevation in plasma S100B concentrations at 24h post-intervention compared to pre-heading baseline (B = 19.57, 95%CI [3.13, 36.02], p = 0.02), whereas all other within-group comparisons in both remained nonsignificant. The data suggest that 10 bouts of acute controlled soccer headings do not elevate S100B concentrations up to 24-hour post-heading. Further dose-response studies with longer follow-up time points may help determine thresholds of acute soccer heading exposure that are related to astrocyte activation. The protocol was registered under ClinicalTrials.gov (NCT03488381; retrospectively registered.).
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Affiliation(s)
- Megan E. Huibregtse
- Department of Kinesiology, Indiana University School of Public Health-Bloomington, Bloomington, Bloomington, Indiana, United States of America
| | - Madeleine K. Nowak
- Department of Kinesiology, Indiana University School of Public Health-Bloomington, Bloomington, Bloomington, Indiana, United States of America
| | - Joseph E. Kim
- Department of Kinesiology, Indiana University School of Public Health-Bloomington, Bloomington, Bloomington, Indiana, United States of America
| | - Rachel M. Kalbfell
- Department of Kinesiology, Indiana University School of Public Health-Bloomington, Bloomington, Bloomington, Indiana, United States of America
| | - Alekhya Koppineni
- Department of Kinesiology, Indiana University School of Public Health-Bloomington, Bloomington, Bloomington, Indiana, United States of America
| | - Keisuke Ejima
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, Indiana, United States of America
| | - Keisuke Kawata
- Department of Kinesiology, Indiana University School of Public Health-Bloomington, Bloomington, Bloomington, Indiana, United States of America
- Program in Neuroscience, College of Arts and Sciences, Indiana University, Bloomington, Indiana, United States of America
- * E-mail:
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Riesco N, Cernuda‐Morollón E, Martínez‐Camblor P, Pérez‐Pereda S, Pascual J. Peripheral, Interictal Serum S100B Levels are Not Increased in Chronic Migraine Patients. Headache 2020; 60:1705-1711. [DOI: 10.1111/head.13919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 06/25/2020] [Accepted: 06/25/2020] [Indexed: 11/30/2022]
Affiliation(s)
- Nuria Riesco
- Service of Neurology University Hospital Central de Asturias Oviedo Spain
| | | | - Pablo Martínez‐Camblor
- Biomedical Data Sciences Department Geisel School of Medicine at Dartmouth Hanover NH USA
| | - Sara Pérez‐Pereda
- Service of Neurology University Hospital Marqués de ValdecillaIDIVAL and University of Cantabria Santander Spain
| | - Julio Pascual
- Service of Neurology University Hospital Marqués de ValdecillaIDIVAL and University of Cantabria Santander Spain
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