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Gouda AR, El-Bassiouny NA, Salahuddin A, Hamouda EH, Kassem AB. Repurposing of high-dose N-acetylcysteine as anti-inflammatory, antioxidant and neuroprotective agent in moderate to severe traumatic brain injury patients: a randomized controlled trial. Inflammopharmacology 2025:10.1007/s10787-025-01706-0. [PMID: 40205270 DOI: 10.1007/s10787-025-01706-0] [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: 02/05/2025] [Accepted: 02/15/2025] [Indexed: 04/11/2025]
Abstract
INTRODUCTION Traumatic brain injury (TBI) refers to an impact of the brain within the skull resulting in an altered mental state. The study aim is to determine the effect of a high dose of N-acetylcysteine (NAC) on biochemical and inflammatory markers of neuronal damage and clinical outcomes in patients with moderate to severe TBI. METHODS A randomized open label-controlled trial was conducted on 40 patients with moderate to severe TBI patients presented to the emergency unit within < 24 h since the trauma occurred and randomized into NAC and control groups 20 patients each. Serum samples for evaluation of biomarkers: malondialdehyde (MDA), interleukin-6 (IL-6), neuron-specific enolase (NSE), and S100B were withdrawn at baseline and on day 7. The patients were followed for 7 days and evaluated clinically by the Glasgow Coma Scale (GCS). RESULTS There was a significant decrease in NSE and MDA levels on day 7 from baseline in NAC group (p < 0.001 and p < 0.001). Also, S100B and IL-6 decreased significantly in NAC group on day 7 from baseline (p = 0.003 and p < 0.001 consequently) compared to control group. Moreover, patients in NAC group showed a significantly shorter length of stay at intensive care unit (ICU) (p = 0.038). There was a significant increase in GCS in NAC group on day 7 from baseline (p = 0.001). CONCLUSION Adjunctive early use of high-dose NAC significantly reduced inflammatory and oxidative markers and had neuroprotective effect which may be a novel treatment option for moderate to severe TBI patients. TRIAL REGISTRATION Pactr.org identifier: (PACTR202209548995270) on 14 September 2022.
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Affiliation(s)
- Alaa Refaat Gouda
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.
| | - Noha A El-Bassiouny
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt
| | - Ahmad Salahuddin
- Biochemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt
- Department of Biochemistry, College of Pharmacy, Al-Ayen Iraqi University, Nasiriyah, Thi-Qar, 64001, Iraq
| | - Emad Hamdy Hamouda
- Critical Care Medicine Department, Faculty of Medicine, University of Alexandria, Alexandria, 21517, Egypt
| | - Amira B Kassem
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt.
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Trnka S, Stejskal P, Jablonsky J, Krahulik D, Pohlodek D, Hrabalek L. S100B protein as a biomarker and predictor in traumatic brain injury. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2024; 168:288-294. [PMID: 37431619 DOI: 10.5507/bp.2023.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/02/2023] [Indexed: 07/12/2023] Open
Abstract
OBJECTIVES To determine the prognostic potential of S100B protein in patients with craniocerebral injury, correlation between S100B protein and time, selected internal diseases, body habitus, polytrauma, and season. METHODS We examined the levels of S100B protein in 124 patients with traumatic brain injury (TBI). RESULTS The S100B protein level 72 h after injury and changes over 72 h afterwards are statistically significant for prediction of a good clinical condition 1 month after injury. The highest sensitivity (81.4%) and specificity (83.3%) for the S100B protein value after 72 h was obtained for a cut-off value of 0.114. For the change after 72 h, that is a decrease in S100B value, the optimal cut-off is 0.730, where the sum of specificity (76.3%) and sensitivity (54.2%) is the highest, or a decrease by 0.526 at the cut-off value, where sensitivity (62.5%) and specificity (62.9%) are more balanced. The S100B values were the highest at baseline; S100B value taken 72 h after trauma negatively correlated with GCS upon discharge or transfer (r=-0.517, P<0.0001). We found no relationship between S100B protein and hypertension, diabetes mellitus, BMI, or season when the trauma occurred. Changes in values and a higher level of S100B protein were demonstrated in polytraumas with a median of 1.070 (0.042; 8.780) μg/L compared to isolated TBI with a median of 0.421 (0.042; 11.230) μg/L. CONCLUSION S100B protein level with specimen collection 72 h after trauma can be used as a complementary marker of patient prognosis.
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Affiliation(s)
- Stefan Trnka
- Department of Neurosurgery, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Premysl Stejskal
- Department of Neurosurgery, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Jakub Jablonsky
- Department of Neurosurgery, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - David Krahulik
- Department of Neurosurgery, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Daniel Pohlodek
- Department of Neurosurgery, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
| | - Lumir Hrabalek
- Department of Neurosurgery, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
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Boucher V, Frenette J, Neveu X, Tardif PA, Mercier É, Chauny JM, Berthelot S, Archambault P, Lee J, Perry JJ, McRae A, Lang E, Moore L, Cameron P, Ouellet MC, de Guise E, Swaine B, Émond M, Le Sage N. Lack of association between four biomarkers and persistent post-concussion symptoms after a mild traumatic brain injury. J Clin Neurosci 2023; 118:34-43. [PMID: 37857062 DOI: 10.1016/j.jocn.2023.10.007] [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: 03/24/2023] [Revised: 08/07/2023] [Accepted: 10/10/2023] [Indexed: 10/21/2023]
Abstract
Approximately 15 % of individuals who sustained a mild Traumatic Brain Injury (TBI) develop persistent post-concussion symptoms (PPCS). We hypothesized that blood biomarkers drawn in the Emergency Department (ED) could help predict PPCS. The main objective of this project was to measure the association between four biomarkers and PPCS at 90 days post mild TBI. We conducted a prospective cohort study in seven Canadian EDs. Patients aged ≥ 14 years presenting to the ED within 24 h of a mild TBI who were discharged were eligible. Clinical data and blood samples were collected in the ED, and a standardized questionnaire was administered 90 days later to assess the presence of symptoms. The following biomarkers were analyzed: S100B protein, Neuron Specific Enolase (NSE), cleaved-Tau (c-Tau) and Glial Fibrillary Acidic Protein (GFAP). The primary outcome measure was the presence of PPCS at 90 days after trauma. Relative risks and Areas Under the Curve (AUC) were computed. A total of 595 patients were included, and 13.8 % suffered from PPCS at 90 days. The relative risk of PPCS was 0.9 (95 % CI: 0.5-1.8) for S100B ≥ 20 pg/mL, 1.0 (95 % CI: 0.6-1.5) for NSE ≥ 200 pg/mL, 3.4 (95 % CI: 0.5-23.4) for GFAP ≥ 100 pg/mL, and 1.0 (95 % CI: 0.6-1.8) for C-Tau ≥ 1500 pg/mL. AUC were 0.50, 0.50, 0.51 and 0.54, respectively. Among mild TBI patients, S100B protein, NSE, c-Tau or GFAP do not seem to predict PPCS. Future research testing of other biomarkers is needed to determine their usefulness in predicting PPCS.
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Affiliation(s)
- Valérie Boucher
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada
| | - Jérôme Frenette
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada; Faculté de médecine, Université Laval, 1050 Av. de la Médecine, Québec, Québec G1V 0A6, Canada
| | - Xavier Neveu
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada
| | - Pier-Alexandre Tardif
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada
| | - Éric Mercier
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada; Faculté de médecine, Université Laval, 1050 Av. de la Médecine, Québec, Québec G1V 0A6, Canada; VITAM-Centre de recherche en santé durable, 2480 Chem. de la Canardière, Québec, Québec G1J 2G1, Canada
| | - Jean-Marc Chauny
- Faculté de médecine, Université de Montréal, 2900 Edouard Montpetit Blvd, Montréal, Québec H3T 1J4, Canada
| | - Simon Berthelot
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada; Faculté de médecine, Université Laval, 1050 Av. de la Médecine, Québec, Québec G1V 0A6, Canada
| | - Patrick Archambault
- Faculté de médecine, Université Laval, 1050 Av. de la Médecine, Québec, Québec G1V 0A6, Canada; VITAM-Centre de recherche en santé durable, 2480 Chem. de la Canardière, Québec, Québec G1J 2G1, Canada; Centre de recherche du CISSS de Chaudière-Appalaches, 143 Rue Wolfe, Lévis, Québec, QC G6V 3Z1, Canada
| | - Jacques Lee
- Sunnybrook Health Science Center, 2075 Bayview Ave, Toronto, Ontario M4N 3M5, Canada; Schwartz-Reisman Emergency Medicine Institute, Mount Sinai Hospital, 600 University Ave, Toronto, Ontario M5G 1X5, Canada
| | - Jeffrey J Perry
- The Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, Ontario K1H 8L6, Canada; Department of Emergency Medicine, University of Ottawa, 75 Laurier Ave E, Ottawa, Ontario K1N 6N5, Canada
| | - Andrew McRae
- Department of Emergency Medicine, University of Calgary, 2500 University Dr NW, Calgary, Alberta T2N 1N4, Canada; Foothills Medical Centre, 1403 29 St NW, Calgary, Alberta T2N 2T9, Canada
| | - Eddy Lang
- Department of Emergency Medicine, University of Calgary, 2500 University Dr NW, Calgary, Alberta T2N 1N4, Canada; Foothills Medical Centre, 1403 29 St NW, Calgary, Alberta T2N 2T9, Canada
| | - Lynne Moore
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada; Faculté de médecine, Université Laval, 1050 Av. de la Médecine, Québec, Québec G1V 0A6, Canada
| | - Peter Cameron
- Alfred Emergency and Trauma Centre, Monash University, 55 Commercial Rd, Melbourne, VIC 3004, Australia
| | - Marie-Christine Ouellet
- Faculté de médecine, Université Laval, 1050 Av. de la Médecine, Québec, Québec G1V 0A6, Canada; Centre interdisciplinaire de recherche en réadaptation et intégration sociale (CIRRIS), 525 Bd Wilfrid-Hamel, Québec, Québec G1M 2S8, Canada
| | - Elaine de Guise
- Département de psychologie, Université de Montréal, 2900, boul. Édouard-Montpetit, Montréal, Québec H3T 1J4, Canada; Centre de recherche interdisciplinaire en réadaptation (CRIR) du Montréal métropolitain, 6363, chemin Hudson, Montréal, Québec H3S 1M9, Canada
| | - Bonnie Swaine
- Faculté de médecine, Université de Montréal, 2900 Edouard Montpetit Blvd, Montréal, Québec H3T 1J4, Canada; Centre de recherche interdisciplinaire en réadaptation (CRIR) du Montréal métropolitain, 6363, chemin Hudson, Montréal, Québec H3S 1M9, Canada
| | - Marcel Émond
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada; Faculté de médecine, Université Laval, 1050 Av. de la Médecine, Québec, Québec G1V 0A6, Canada; VITAM-Centre de recherche en santé durable, 2480 Chem. de la Canardière, Québec, Québec G1J 2G1, Canada
| | - Natalie Le Sage
- CHU de Québec-Université Laval Research Centre, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada; Faculté de médecine, Université Laval, 1050 Av. de la Médecine, Québec, Québec G1V 0A6, Canada; VITAM-Centre de recherche en santé durable, 2480 Chem. de la Canardière, Québec, Québec G1J 2G1, Canada.
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Maroto-García J, Martínez-Escribano A, Delgado-Gil V, Mañez M, Mugueta C, Varo N, García de la Torre Á, Ruiz-Galdón M. Biochemical biomarkers for multiple sclerosis. Clin Chim Acta 2023; 548:117471. [PMID: 37419300 DOI: 10.1016/j.cca.2023.117471] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 07/04/2023] [Accepted: 07/04/2023] [Indexed: 07/09/2023]
Abstract
INTRODUCTION Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system. Although there is currently no definite cure for MS, new therapies have recently been developed based on a continuous search for new biomarkers. DEVELOPMENT MS diagnosis relies on the integration of clinical, imaging and laboratory findings as there is still no singlepathognomonicclinical feature or diagnostic laboratory biomarker. The most commonly laboratory test used is the presence of immunoglobulin G oligoclonal bands (OCB) in cerebrospinal fluid of MS patients. This test is now included in the 2017 McDonald criteria as a biomarker of dissemination in time. Nevertheless, there are other biomarkers currently in use such as kappa free light chain, which has shown higher sensitivity and specificity for MS diagnosis than OCB. In addition, other potential laboratory tests involved in neuronal damage, demyelination and/or inflammation could be used for detecting MS. CONCLUSIONS CSF and serum biomarkers have been reviewed for their use in MS diagnosis and prognosis to stablish an accurate and prompt MS diagnosis, crucial to implement an adequate treatment and to optimize clinical outcomes over time.
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Affiliation(s)
- Julia Maroto-García
- Biochemistry Department, Clínica Universidad de Navarra, Spain; Department of Biochemistry and Molecular Biology. Faculty of Medicine. University of Malaga, Spain.
| | - Ana Martínez-Escribano
- Department of Biochemistry and Molecular Biology. Faculty of Medicine. University of Malaga, Spain; Laboratory Medicine, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-ARRIXACA, Murcia, Spain
| | - Virginia Delgado-Gil
- Neurology Department, Hospital Universitario Virgen de la Victoria, Malaga, Spain
| | - Minerva Mañez
- Neurology Department, Hospital Universitario Virgen de la Victoria, Malaga, Spain
| | - Carmen Mugueta
- Biochemistry Department, Clínica Universidad de Navarra, Spain
| | - Nerea Varo
- Biochemistry Department, Clínica Universidad de Navarra, Spain
| | - Ángela García de la Torre
- Clinical Analysis Service, Hospital Universitario Virgen de la Victoria, Malaga, Spain; The Biomedical Research Institute of Malaga (IBIMA), Malaga, Spain
| | - Maximiliano Ruiz-Galdón
- Department of Biochemistry and Molecular Biology. Faculty of Medicine. University of Malaga, Spain; Clinical Analysis Service, Hospital Universitario Virgen de la Victoria, Malaga, Spain; The Biomedical Research Institute of Malaga (IBIMA), Malaga, Spain
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Wang Q, Xu M, Xiao M, Luan X, Chen H, Ruan Y, Wang L, Tu Y, Huang G, He J. The relationship between serum levels of S-100β and anxiety symptoms in patients with acute stroke. Psychogeriatrics 2022; 22:291-298. [PMID: 35229415 DOI: 10.1111/psyg.12799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 11/22/2021] [Accepted: 12/01/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Post-stroke anxiety (PSA) is a common neuropsychiatric affective disorder occurring after a stroke. Animal experiments have indicated that serum S-100β levels are closely related to anxiety disorder. No clinical study has been done to explore the relationship between serum S-100β levels and anxiety symptoms in patients with acute stroke. The aim of our study was to investigate the association between serum S-100β levels and PSA. METHODS One hundred twenty-six acute stroke patients were recruited and followed up for 1 month. Blood samples were collected within 24 h after admission. The levels of serum S-100β were measured by enzyme-linked immunosorbent assays. Patients with significant clinical symptoms of anxiety and a Hamilton Anxiety Rating Scale score >7 at 1 month after stroke were diagnosed as PSA. RESULTS Serum S-100β levels in the non-PSA group were lower than the PSA group (838.97 (678.20-993.59) ng/L vs. 961.87 (796.09-1479.59) ng/L, Z = -2.661, P = 0.008). In multivariate analyses, we found that decreased risk of PSA was associated with low tertile serum S-100β levels (≤753.8 ng/L, OR 0.062, 95% CI 0.008-0.475, P = 0.007). CONCLUSIONS Low serum S-100β levels at admission may be associated with the decreased risk of PSA.
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Affiliation(s)
- Qiongzhang Wang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Minjie Xu
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Meijuan Xiao
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaoqian Luan
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huijun Chen
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yiting Ruan
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liuyuan Wang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yujie Tu
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guiqian Huang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jincai He
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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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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Whitehouse DP, Monteiro M, Czeiter E, Vyvere TV, Valerio F, Ye Z, Amrein K, Kamnitsas K, Xu H, Yang Z, Verheyden J, Das T, Kornaropoulos EN, Steyerberg E, Maas AIR, Wang KKW, Büki A, Glocker B, Menon DK, Newcombe VFJ. Relationship of admission blood proteomic biomarkers levels to lesion type and lesion burden in traumatic brain injury: A CENTER-TBI study. EBioMedicine 2022; 75:103777. [PMID: 34959133 PMCID: PMC8718895 DOI: 10.1016/j.ebiom.2021.103777] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 11/12/2021] [Accepted: 12/10/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND We aimed to understand the relationship between serum biomarker concentration and lesion type and volume found on computed tomography (CT) following all severities of TBI. METHODS Concentrations of six serum biomarkers (GFAP, NFL, NSE, S100B, t-tau and UCH-L1) were measured in samples obtained <24 hours post-injury from 2869 patients with all severities of TBI, enrolled in the CENTER-TBI prospective cohort study (NCT02210221). Imaging phenotypes were defined as intraparenchymal haemorrhage (IPH), oedema, subdural haematoma (SDH), extradural haematoma (EDH), traumatic subarachnoid haemorrhage (tSAH), diffuse axonal injury (DAI), and intraventricular haemorrhage (IVH). Multivariable polynomial regression was performed to examine the association between biomarker levels and both distinct lesion types and lesion volumes. Hierarchical clustering was used to explore imaging phenotypes; and principal component analysis and k-means clustering of acute biomarker concentrations to explore patterns of biomarker clustering. FINDINGS 2869 patient were included, 68% (n=1946) male with a median age of 49 years (range 2-96). All severities of TBI (mild, moderate and severe) were included for analysis with majority (n=1946, 68%) having a mild injury (GCS 13-15). Patients with severe diffuse injury (Marshall III/IV) showed significantly higher levels of all measured biomarkers, with the exception of NFL, than patients with focal mass lesions (Marshall grades V/VI). Patients with either DAI+IVH or SDH+IPH+tSAH, had significantly higher biomarker concentrations than patients with EDH. Higher biomarker concentrations were associated with greater volume of IPH (GFAP, S100B, t-tau;adj r2 range:0·48-0·49; p<0·05), oedema (GFAP, NFL, NSE, t-tau, UCH-L1;adj r2 range:0·44-0·44; p<0·01), IVH (S100B;adj r2 range:0.48-0.49; p<0.05), Unsupervised k-means biomarker clustering revealed two clusters explaining 83·9% of variance, with phenotyping characteristics related to clinical injury severity. INTERPRETATION Interpretation: Biomarker concentration within 24 hours of TBI is primarily related to severity of injury and intracranial disease burden, rather than pathoanatomical type of injury. FUNDING CENTER-TBI is funded by the European Union 7th Framework programme (EC grant 602150).
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Affiliation(s)
- Daniel P Whitehouse
- University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
| | - Miguel Monteiro
- Biomedical Image Analysis Group, Department of Computing, Imperial College, London, UK
| | - Endre Czeiter
- Department of Neurosurgery, Medical School, University of Pécs, Rét u. 2, H-7623 Pécs, Hungary; Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary; MTA-PTE Clinical Neuroscience MR Research Group; Pécs, Hungary
| | - Thijs Vande Vyvere
- Research and Development, Icometrix, Leuven, Belgium; Department of Radiology, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium
| | - Fernanda Valerio
- University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
| | - Zheng Ye
- University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
| | - Krisztina Amrein
- Department of Neurosurgery, Medical School, University of Pécs, Rét u. 2, H-7623 Pécs, Hungary; Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary
| | | | - Haiyan Xu
- Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of Emergency Medicine, Psychiatry and Neuroscience, University of Florida, McKnight Brain Institute, L4-100L 1149 South Newell Drive, Gainesville, FL 32611, USA
| | - Zhihui Yang
- Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of Emergency Medicine, Psychiatry and Neuroscience, University of Florida, McKnight Brain Institute, L4-100L 1149 South Newell Drive, Gainesville, FL 32611, USA
| | - Jan Verheyden
- Research and Development, Icometrix, Leuven, Belgium
| | - Tilak Das
- Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
| | | | - Ewout Steyerberg
- Center for Medical Decision Making, Department of Public Health, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands
| | - Andrew I R Maas
- Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Wijlrijkstraat 10, 2650 Edegem, Belgium
| | - Kevin K W Wang
- Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of Emergency Medicine, Psychiatry and Neuroscience, University of Florida, McKnight Brain Institute, L4-100L 1149 South Newell Drive, Gainesville, FL 32611, USA; Brain Rehabilitation Research Center, Malcom Randall Veterans Affairs Medical Center (VAMC), 1601 SW, Archer Rd. Gainesville FL 32608, USA
| | - András Büki
- Department of Neurosurgery, Medical School, University of Pécs, Rét u. 2, H-7623 Pécs, Hungary; Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary
| | - Ben Glocker
- Biomedical Image Analysis Group, Department of Computing, Imperial College, London, UK
| | - David K Menon
- University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK
| | - Virginia F J Newcombe
- University Division of Anaesthesia, Department of Medicine, University of Cambridge, UK.
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8
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Zhang K, Wang Z, Zhu K, Dong S, Pan X, Sun L, Li Q. Neurofilament Light Chain Protein Is a Predictive Biomarker for Stroke After Surgical Repair for Acute Type A Aortic Dissection. Front Cardiovasc Med 2021; 8:754801. [PMID: 34859071 PMCID: PMC8631920 DOI: 10.3389/fcvm.2021.754801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 10/20/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Although great progress has been made in surgery and perioperative care, stroke is still a fatal complication of acute type A aortic dissection (ATAAD). Serum biomarkers may help assess brain damage and predict patient's prognosis. Methods: From March, 2019 to January, 2020, a total of 88 patients underwent surgical treatment at the Department of Cardiovascular Surgery of Beijing Anzhen Hospital, China, and were enrolled in this study. Patients were divided into two groups according to whether they had suffered a stroke after the operation. Blood samples were collected at 8 time points within 3 days after surgery to determine the level of S100β, neuron-specific enolase (NSE) and neurofilament light chain protein (NFL). Receiver operating characteristic curves (ROC) were established to explore the biomarker predictive value in stroke. The area under the curve (AUC) was used to quantify the ROC curve. Results: The patient average age was 48.1 ± 11.0 years old and 70 (79.6%) patients were male. Fifteen (17.0%) patients suffered stroke after surgery. The NFL levels of patients in the stroke group at 12 and 24 h after surgery were significantly higher than those in the non-stroke group (all P < 0.001). However, the NSE and S100β levels did not differ significantly at any time point between the two groups. The predictive value of NFL was the highest at 12 and 24 h after surgery, and the AUC was 0.834 (95% CI, 0.723-0.951, P < 0.001) and 0.748 (95% CI, 0.603-0.894, P = 0.004), respectively. Its sensitivity and specificity at 12 h were 86.7 and 71.6%, respectively. The NFL cutoff value for the diagnosis of stroke at 12 h after surgery was 16.042 ng/ml. Conclusions: This study suggests that NFL is an early and sensitive serum marker for predicting post-operative neurological prognosis of ATAAD patients. Further studies, including large-scale prospective clinical trials, are necessary to test whether the NFL can be used as a biomarker for clinical decision-making.
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Affiliation(s)
- Kai Zhang
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China.,Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zhu Wang
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China
| | - Kai Zhu
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Songbo Dong
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xudong Pan
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Lizhong Sun
- Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Qing Li
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, China
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9
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Wan Z, Li Y, Ye H, Zi Y, Zhang G, Wang X. Plasma S100β and neuron-specific enolase, but not neuroglobin, are associated with early cognitive dysfunction after total arch replacement surgery: A pilot study. Medicine (Baltimore) 2021; 100:e25446. [PMID: 33847649 PMCID: PMC8051968 DOI: 10.1097/md.0000000000025446] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 03/08/2021] [Indexed: 01/04/2023] Open
Abstract
To investigate whether plasma concentrations of S100β protein, neuron-specific enolase (NSE), and neuroglobin (NGB) correlate with early postoperative cognitive dysfunction (POCD) in patients undergoing total arch replacement.This prospective study analyzed 40 patients who underwent total arch replacement combined with stented elephant trunk implantation at our hospital between March 2017 and January 2019. Cognitive function was assessed using the Mini-mental State Examination (MMSE) preoperatively, on the day after extubation and on day 7 after surgery. Plasma levels of S100β, NSE, and NGB POCD were assayed preoperatively and at 1, 6, and 24 hours after cardiopulmonary bypass. POCD was defined as a decrease of at least 1 unit in the MMSE score from before surgery until day 7, and patients were stratified into those who experienced POCD or not. The 2 groups were compared in clinicodemographic characteristics and plasma levels of the 3 proteins.Plasma levels of all 3 biomarkers increased significantly during and after cardiopulmonary bypass. Levels of S100β and NSE, but not NGB, were significantly higher in the 15 patients who showed POCD than in the remainder who did not. For prediction of early POCD, S100β showed an area under the receiver operating characteristic curve (AUC) of 0.71 (95% confidence interval [CI] 0.55-0.87), sensitivity of 48%, and specificity of 87%. The corresponding values for NSE were 0.77 (95%CI 0.60-0.94), 92%, and 67%. Together, S100β and NSE showed an AUC of 0.81 (95%CI 0.66-0.96), sensitivity of 73%, and specificity of 80%. NGB did not significantly predict early POCD (AUC 0.62, 95%CI 0.43-0.80).Plasma S100β protein and NSE, but not NGB, may help predict early POCD after total arch replacement.
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Affiliation(s)
- Zilin Wan
- Department of Cardiovascular Anesthesiology
| | - Yaxiong Li
- Department of Cardiovascular Surgery, Yan’An Hospital, Kunming Medical University, Kunming, 650051, Yunnan, China
| | - Huishun Ye
- Department of Cardiovascular Anesthesiology
| | - Yunfeng Zi
- Department of Cardiovascular Surgery, Yan’An Hospital, Kunming Medical University, Kunming, 650051, Yunnan, China
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10
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Blais Lécuyer J, Mercier É, Tardif PA, Archambault PM, Chauny JM, Berthelot S, Frenette J, Perry J, Stiell I, Émond M, Lee J, Lang E, McRae A, Boucher V, Le Sage N. S100B protein level for the detection of clinically significant intracranial haemorrhage in patients with mild traumatic brain injury: a subanalysis of a prospective cohort study. Emerg Med J 2020; 38:285-289. [PMID: 33355233 PMCID: PMC7982939 DOI: 10.1136/emermed-2020-209583] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 10/21/2020] [Accepted: 11/08/2020] [Indexed: 11/18/2022]
Abstract
Background Clinical assessment of patients with mild traumatic brain injury (mTBI) is challenging and overuse of head CT in the ED is a major problem. Several studies have attempted to reduce unnecessary head CTs following a mTBI by identifying new tools aiming to predict intracranial bleeding. Higher levels of S100B protein have been associated with intracranial haemorrhage following a mTBI in previous literature. The main objective of this study is to assess whether plasma S100B protein level is associated with clinically significant brain injury and could be used to reduce the number of head CT post-mTBI. Methods Study design: secondary analysis of a prospective multicentre cohort study conducted between 2013 and 2016 in five Canadian EDs. Inclusion criteria: non-hospitalised patients with mTBI with a GCS score of 13–15 in the ED and a blood sample drawn within 24 hours after the injury. Data collected: sociodemographic and clinical data were collected in the ED. S100B protein was analysed using ELISA. All CT scans were reviewed by a radiologist blinded to the biomarker results. Main outcome: the presence of clinically important brain injury. Results 476 patients were included. Mean age was 41±18 years old and 150 (31.5%) were women. Twenty-four (5.0%) patients had a clinically significant intracranial haemorrhage. Thirteen patients (2.7%) presented a non-clinically significant brain injury. A total of 37 (7.8%) brain injured patients were included in our study. S100B median value (Q1–Q3) was: 0.043 µg/L (0.008–0.080) for patients with clinically important brain injury versus 0.039 µg/L (0.023–0.059) for patients without clinically important brain injury. Sensitivity and specificity of the S100B protein level, if used alone to detect clinically important brain injury, were 16.7% (95% CI 4.7% to 37.4%) and 88.5% (95% CI 85.2% to 91.3%), respectively. Conclusion Plasma S100B protein level was not associated with clinically significant intracranial lesion in patients with mTBI.
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Affiliation(s)
- Julien Blais Lécuyer
- Department of Family Medicine and Emergency Medicine, Université Laval, Quebec, Quebec, Canada.,Axe de recherche en Santé des populations et pratiques optimales en santé, CHU de Quebec-Universite Laval Research Center, Quebec, Quebec, Canada
| | - Éric Mercier
- Department of Family Medicine and Emergency Medicine, Université Laval, Quebec, Quebec, Canada.,Axe de recherche en Santé des populations et pratiques optimales en santé, CHU de Quebec-Universite Laval Research Center, Quebec, Quebec, Canada
| | - Pier-Alexandre Tardif
- Axe de recherche en Santé des populations et pratiques optimales en santé, CHU de Quebec-Universite Laval Research Center, Quebec, Quebec, Canada
| | - Patrick M Archambault
- Department of Anesthesiology and Critical Care Medicine, Université Laval, Quebec, Quebec, Canada.,Chaudiere-Appalaches Integrated Health and Social Services Center, Lévis, Quebec, Canada
| | - Jean-Marc Chauny
- Department of family medicine and emergency medicine, University of Montreal, Montreal, Quebec, Canada
| | - Simon Berthelot
- Axe de recherche en Santé des populations et pratiques optimales en santé, CHU de Quebec-Universite Laval Research Center, Quebec, Quebec, Canada
| | - Jérôme Frenette
- Department of Family Medicine and Emergency Medicine, Université Laval, Quebec, Quebec, Canada
| | - Jeff Perry
- Department of Family Medicine and Emergency Medicine, Université Laval, Quebec, Quebec, Canada.,Department of emergency medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Ian Stiell
- Department of emergency medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Marcel Émond
- Department of Family Medicine and Emergency Medicine, Université Laval, Quebec, Quebec, Canada.,Axe de recherche en Santé des populations et pratiques optimales en santé, CHU de Quebec-Universite Laval Research Center, Quebec, Quebec, Canada
| | - Jacques Lee
- Schwartz/Reisman Emergency Medicine Institute, Toronto, Ontario, Canada
| | - Eddy Lang
- Department of emergency medicine, University of Calgary, Calgary, Alberta, Canada
| | - Andrew McRae
- Department of emergency medicine, University of Calgary, Calgary, Alberta, Canada
| | - Valérie Boucher
- Axe de recherche en Santé des populations et pratiques optimales en santé, CHU de Quebec-Universite Laval Research Center, Quebec, Quebec, Canada
| | - Natalie Le Sage
- Department of Family Medicine and Emergency Medicine, Université Laval, Quebec, Quebec, Canada .,Axe de recherche en Santé des populations et pratiques optimales en santé, CHU de Quebec-Universite Laval Research Center, Quebec, Quebec, Canada
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11
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Chai O, Mazaki-Tovi M, Klainbart S, Kelmer E, Shipov A, Shamir MH. Serum Concentrations of Neuron-Specific Enolase in Dogs Following Traumatic Brain Injury. J Comp Pathol 2020; 179:45-51. [PMID: 32958147 DOI: 10.1016/j.jcpa.2020.06.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/15/2020] [Accepted: 06/18/2020] [Indexed: 01/15/2023]
Abstract
The ability to make an accurate prognosis, which is a prerequisite for treatment decisions, is very limited in dogs with traumatic brain injury (TBI). To determine whether serum concentrations of neuron-specific enolase (NSE) have prognostic value in dogs following TBI, we conducted a prospective, observational, controlled clinical study in an intensive care unit of a university teaching hospital. The study population comprised 24 dogs admitted to the hospital within 72 h of a known event of TBI between January 2010 and January 2015, as well as 25 control healthy shelter dogs admitted for elective neutering. Seventeen injured dogs (70%) survived to discharge, four were euthanized and three died within 48 h. Serum samples were obtained from all dogs (in injured dogs, within 72 h of TBI) and NSE concentrations were measured using enzyme-linked immonosorbent assay. Associations between NSE levels and outcome, Modified Glasgow Coma Scale, time to sampling, age or haemolysis scale were determined. Mean serum NSE concentrations were decreased in dogs with TBI compared with healthy controls (19.4 ± 4.14 ng/ml vs. 24.9 ± 4.6 ng/ml, P <0.001). No association was found between serum NSE concentrations and either survival or severity of neurological impairment. A negative correlation was found between serum NSE concentrations and time from trauma to blood collection (r = -0.50, P = 0.022). These results indicate that serum NSE concentration in dogs following TBI is not an effective marker for severity or outcome. Further studies are warranted to standardize serum NSE measurements in dogs and to determine the peak and half-life levels of this potential biomarker.
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Affiliation(s)
- O Chai
- Koret School of Veterinary Medicine, Veterinary Teaching Hospital, Hebrew University of Jerusalem, Rehovot, Israel.
| | - M Mazaki-Tovi
- Koret School of Veterinary Medicine, Veterinary Teaching Hospital, Hebrew University of Jerusalem, Rehovot, Israel
| | - S Klainbart
- Koret School of Veterinary Medicine, Veterinary Teaching Hospital, Hebrew University of Jerusalem, Rehovot, Israel
| | - E Kelmer
- Koret School of Veterinary Medicine, Veterinary Teaching Hospital, Hebrew University of Jerusalem, Rehovot, Israel
| | - A Shipov
- Koret School of Veterinary Medicine, Veterinary Teaching Hospital, Hebrew University of Jerusalem, Rehovot, Israel
| | - M H Shamir
- Koret School of Veterinary Medicine, Veterinary Teaching Hospital, Hebrew University of Jerusalem, Rehovot, Israel
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12
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Guzelcicek A, Gönel A, Koyuncu I, Cigdem G, Kose D, Karadag M, Cadirci D. Investigating the Levels of Brain-Specific Proteins in Hydrocephalus Patients. Comb Chem High Throughput Screen 2020; 24:409-414. [PMID: 32691706 DOI: 10.2174/1386207323666200720093245] [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: 04/06/2020] [Revised: 05/04/2020] [Accepted: 05/28/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Hydrocephalus, a common brain disorder in children, can cause permanent brain damage. A timely diagnosis of this disorder is crucial. OBJECTIVE The aim of this study was to evaluate the levels of S-100, CK-18, and NSE brainspecific proteins in patients with hydrocephalus. We examined the levels of these proteins in the blood samples of hydrocephalic patients. METHODS The study was conducted on the hydrocephalus (n = 31) patients and a healthy control group (n = 30). A Receiver Operating Characteristic (ROC) curve was used to assess the validity of the NSE, CK-18, and S100B to differentiate between the hydrocephalus and the control groups. The suitability of the data to the normal distribution was tested with the Shapiro Wilk test, and the Student t-test was used to compare the characteristics of the normal distribution in two independent groups. The individuals in the hydrocephalus and control groups had similar values in terms of age, height, and weight. RESULTS It was observed that NSE, CK-18, and S100B mean values of the individuals in the hydrocephalus group were significantly higher than NSE, CK-18, and S100B mean values of the control group. CONCLUSION Experiments have shown that the levels of these proteins increase significantly in hydrocephalus patients compared to the healthy group. These three parameters can be considered as important markers in the diagnosis of hydrocephalus.
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Affiliation(s)
- Ahmet Guzelcicek
- Department of Pediatrics, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Ataman Gönel
- Department of Medicinal Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Ismail Koyuncu
- Department of Medicinal Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Gulyara Cigdem
- Department of Neurosurgery, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Dogan Kose
- Department of Pediatrics, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Mehmet Karadag
- Department of Biostatistics, Mustafa Kemal University, Faculty of Medicine, Hatay, Turkey
| | - Dursun Cadirci
- Department of Family Medicine, Faculty of Medicine, Harran University, Sanliurfa, Turkey
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13
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Gozt A, Licari M, Halstrom A, Milbourn H, Lydiard S, Black A, Arendts G, Macdonald S, Song S, MacDonald E, Vlaskovsky P, Burrows S, Bynevelt M, Pestell C, Fatovich D, Fitzgerald M. Towards the Development of an Integrative, Evidence-Based Suite of Indicators for the Prediction of Outcome Following Mild Traumatic Brain Injury: Results from a Pilot Study. Brain Sci 2020; 10:brainsci10010023. [PMID: 31906443 PMCID: PMC7017246 DOI: 10.3390/brainsci10010023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/16/2019] [Accepted: 12/30/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Persisting post-concussion symptoms (PPCS) is a complex, multifaceted condition in which individuals continue to experience the symptoms of mild traumatic brain injury (mTBI; concussion) beyond the timeframe that it typically takes to recover. Currently, there is no way of knowing which individuals may develop this condition. Method: Patients presenting to a hospital emergency department (ED) within 48 h of sustaining a mTBI underwent neuropsychological assessment and demographic, injury-related information and blood samples were collected. Concentrations of blood-based biomarkers neuron specific enolase, neurofilament protein-light, and glial fibrillary acidic protein were assessed, and a subset of patients also underwent diffusion tensor–magnetic resonance imaging; both relative to healthy controls. Individuals were classified as having PPCS if they reported a score of 25 or higher on the Rivermead Postconcussion Symptoms Questionnaire at ~28 days post-injury. Univariate exact logistic regression was performed to identify measures that may be predictive of PPCS. Neuroimaging data were examined for differences in fractional anisotropy (FA) and mean diffusivity in regions of interest. Results: Of n = 36 individuals, three (8.33%) were classified as having PPCS. Increased performance on the Repeatable Battery for the Assessment of Neuropsychological Status Update Total Score (OR = 0.81, 95% CI: 0.61–0.95, p = 0.004), Immediate Memory (OR = 0.79, 95% CI: 0.56–0.94, p = 0.001), and Attention (OR = 0.86, 95% CI: 0.71–0.97, p = 0.007) indices, as well as faster completion of the Trails Making Test B (OR = 1.06, 95% CI: 1.00–1.12, p = 0.032) at ED presentation were associated with a statistically significant decreased odds of an individual being classified as having PPCS. There was no significant association between blood-based biomarkers and PPCS in this small sample, although glial fibrillary acidic protein (GFAP) was significantly increased in individuals with mTBI relative to healthy controls. Furthermore, relative to healthy age and sex-matched controls (n = 8), individuals with mTBI (n = 14) had higher levels of FA within the left inferior frontal occipital fasciculus (t (18.06) = −3.01, p = 0.008). Conclusion: Performance on neuropsychological measures may be useful for predicting PPCS, but further investigation is required to elucidate the utility of this and other potential predictors.
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Affiliation(s)
- Aleksandra Gozt
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia; (A.G.); (A.B.); (C.P.)
- Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Melissa Licari
- Telethon Kids Institute, West Perth, WA 6005, Australia;
| | - Alison Halstrom
- School of Biological Sciences, The University of Western Australia, Crawley, WA 6009, Australia; (A.H.); (H.M.); (S.L.)
| | - Hannah Milbourn
- School of Biological Sciences, The University of Western Australia, Crawley, WA 6009, Australia; (A.H.); (H.M.); (S.L.)
| | - Stephen Lydiard
- School of Biological Sciences, The University of Western Australia, Crawley, WA 6009, Australia; (A.H.); (H.M.); (S.L.)
| | - Anna Black
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia; (A.G.); (A.B.); (C.P.)
- Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
| | - Glenn Arendts
- Emergency Medicine, The University of Western Australia, Crawley, WA 6009, Australia; (G.A.); (S.M.); (D.F.)
- Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Nedlands, WA 6000, Australia;
| | - Stephen Macdonald
- Emergency Medicine, The University of Western Australia, Crawley, WA 6009, Australia; (G.A.); (S.M.); (D.F.)
- Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Nedlands, WA 6000, Australia;
- Emergency Department, Royal Perth Hospital, Perth, WA 6000, Australia
| | - Swithin Song
- Radiology Department, Royal Perth Hospital, Perth, WA 6000, Australia;
| | - Ellen MacDonald
- Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Nedlands, WA 6000, Australia;
- Emergency Department, Royal Perth Hospital, Perth, WA 6000, Australia
| | - Philip Vlaskovsky
- School of Medicine, The University of Western Australia, Crawley, WA 6009, Australia; (P.V.); (S.B.)
| | - Sally Burrows
- School of Medicine, The University of Western Australia, Crawley, WA 6009, Australia; (P.V.); (S.B.)
| | - Michael Bynevelt
- School of Surgery, The University of Western Australia, Crawley, WA 6009, Australia;
- Neurological Intervention and Imaging Service of Western Australia, Sir Charles Gardener Hospital, Nedlands, WA 6009, Australia
| | - Carmela Pestell
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia; (A.G.); (A.B.); (C.P.)
- School of Psychological Science, The University of Western Australia, Crawley, WA 6009, Australia
| | - Daniel Fatovich
- Emergency Medicine, The University of Western Australia, Crawley, WA 6009, Australia; (G.A.); (S.M.); (D.F.)
- Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Nedlands, WA 6000, Australia;
- Emergency Department, Royal Perth Hospital, Perth, WA 6000, Australia
| | - Melinda Fitzgerald
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia; (A.G.); (A.B.); (C.P.)
- Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
- School of Biological Sciences, The University of Western Australia, Crawley, WA 6009, Australia; (A.H.); (H.M.); (S.L.)
- Correspondence: ; Tel.: +61-467-729-300
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14
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Chitinase-3-Like Protein 1, Serum Amyloid A1, C-Reactive Protein, and Procalcitonin Are Promising Biomarkers for Intracranial Severity Assessment of Traumatic Brain Injury: Relationship with Glasgow Coma Scale and Computed Tomography Volumetry. World Neurosurg 2019; 134:e120-e143. [PMID: 31606503 DOI: 10.1016/j.wneu.2019.09.143] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/24/2019] [Accepted: 09/26/2019] [Indexed: 11/23/2022]
Abstract
OBJECTIVE The volume and location of intracranial hematomas are well-known prognostic factors for traumatic brain injury. The aim of this study was to determine the relationship of serum biomarkers S100β, glial fibrillary acidic protein, neuron-specific enolase, total tau, phosphorylated neurofilament heavy chain, serum amyloid A1 (SAA1), C-reactive protein, procalcitonin (PCT), and chitinase-3-like protein 1 (YKL-40) with traumatic brain injury severity and the amount and location of hemorrhagic traumatic lesions. METHODS A prospective observational cohort of 115 patients with a Glasgow Coma Scale (GCS) score of 3-15 were evaluated. Intracranial lesion volume was measured from the semiautomatic segmentation of hematoma on computed tomography using Analyze software. The establishment of possible biomarker cutoff points for intracranial lesion detection was estimated using the Youden Index (J) obtained from the area under the receiver operating characteristic curve. RESULTS SAA1, YKL-40, PCT, and S100β showed the most robust association with level of consciousness, both with total GCS and motor score. Biomarkers significantly correlated with volumetric measurements of subdural hematoma, traumatic subarachnoid hemorrhage, intraparenchymal hemorrhage, intraventricular hemorrhage, and total amount of bleeding. The type of intracranial hemorrhage was associated with various release patterns of neurobiochemical markers. CONCLUSIONS YKL-40, SAA1, C-reactive protein, and PCT combined with S100β were the most promising biomarkers to determine the presence, location, and extent of traumatic intracranial lesions. Combination of biomarkers further increased the discriminatory capacity for the detection of intracranial bleeding.
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15
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Frankel M, Fan L, Yeatts SD, Jeromin A, Vos PE, Wagner AK, Wolf BJ, Pauls Q, Lunney M, Merck LH, Hall CL, Palesch YY, Silbergleit R, Wright DW. Association of Very Early Serum Levels of S100B, Glial Fibrillary Acidic Protein, Ubiquitin C-Terminal Hydrolase-L1, and Spectrin Breakdown Product with Outcome in ProTECT III. J Neurotrauma 2019; 36:2863-2871. [PMID: 30794101 DOI: 10.1089/neu.2018.5809] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Rapid risk-stratification of patients with acute traumatic brain injury (TBI) would inform management decisions and prognostication. The objective of this serum biomarker study (Biomarkers of Injury and Outcome [BIO]-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment [ProTECT]) was to test the hypothesis that serum biomarkers of structural brain injury, measured at a single, very early time-point, add value beyond relevant clinical covariates when predicting unfavorable outcome 6 months after moderate-to-severe acute TBI. BIO-ProTECT utilized prospectively collected samples obtained from subjects with moderate-to-severe TBI enrolled in the ProTECT III clinical trial of progesterone. Serum samples were obtained within 4 h after injury. Glial fibrillary acidic protein (GFAP), S100B, αII-spectrin breakdown product of molecular weight 150 (SBDP150), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) were measured. The association between log-transformed biomarker levels and poor outcome, defined by a Glasgow Outcome Scale-Extended (GOS-E) score of 1-4 at 6 months post-injury, were estimated via logistic regression. Prognostic models and a biomarker risk score were developed using bootstrapping techniques. Of 882 ProTECT III subjects, samples were available for 566. Each biomarker was associated with 6-month GOS-E (p < 0.001). Compared with a model containing baseline patient variables/characteristics, inclusion of S100B and GFAP significantly improved prognostic capacity (p ≤ 0.05 both comparisons); conversely, UCH-L1 and SBDP did not. A final predictive model incorporating baseline patient variables/characteristics and biomarker data (S100B and GFAP) had the best prognostic capability (area under the curve [AUC] = 0.85, 95% confidence interval [CI]: CI 0.81-0.89). Very early measurements of brain-specific biomarkers are independently associated with 6-month outcome after moderate-to-severe TBI and enhance outcome prediction.
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Affiliation(s)
- Michael Frankel
- Department of Neurology, Emory University School of Medicine and Grady Hospital, Atlanta, Georgia
| | - Liqiong Fan
- Novartis Institutes of Biomedical Research, Cambridge, Massachusetts
| | - Sharon D Yeatts
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | | | - Pieter E Vos
- Department of Neurology, Slingeland Hospital Doetinchem, The Netherlands
| | - Amy K Wagner
- Department of Physical Medicine and Rehabilitation and Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Bethany J Wolf
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Qi Pauls
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | | | - Lisa H Merck
- Division of Emergency Neurosciences and Critical Care Research, The Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island
| | - Casey L Hall
- Department of Neurology, Emory University School of Medicine and Grady Hospital, Atlanta, Georgia
| | - Yuko Y Palesch
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Robert Silbergleit
- Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan
| | - David W Wright
- Department of Emergency Medicine, Emory University School of Medicine and Grady Hospital, Atlanta, Georgia
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16
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Park DW, Park SH, Hwang SK. Serial measurement of S100B and NSE in pediatric traumatic brain injury. Childs Nerv Syst 2019; 35:343-348. [PMID: 30171330 DOI: 10.1007/s00381-018-3955-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 08/19/2018] [Indexed: 10/28/2022]
Abstract
PURPOSE Increased serum biomakers, such as S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE), are associated with traumatic brain injury (TBI). The purpose of this study is to investigate the serum levels of S100B and NSE in pediatric TBI patients and to predict a clinical outcome. METHODS Peripheral venous blood was collected within 6 h of injury and at 1 week to measure S100B and NSE. The serum S100B and NSE levels were measured using commercially available enzyme-linked immunosorbent assay kits. The authors divided participants into two groups at admission: a favorable group (patients with Glasgow Coma Scale [GCS] scores of 10-15) and an unfavorable group (patients with GCS scores of less than 9). Both S100B and NSE levels were compared between the two groups at the time of admission and 1 week later. RESULTS Ten pediatric patients were enrolled (5 in the favorable group, 5 in the unfavorable group). The median serum S100B level of 134.21 pg/ml (range, 51.00-789.65 pg/ml) in patients with TBI at admission dropped to 41.49 pg/ml (range, 25.65-260.93 pg/ml) after 1 week, with significant differences between the traumatic event and 1 week later (p = 0.007). The median serum NSE level of 14.76 ng/ml (range, 6.48-21.23 ng/ml) in patients with TBI at admission was higher than that after 1 week (4.96 ng/ml, range, 3.01-31.21 ng/ml), with significant differences (p = 0.015). A significant difference was observed in S100B after 1 week between patients in the favorable and unfavorable groups (p = 0.047). One patient whose serum S100B and NSE levels were elevated 1 week after TBI eventually died. CONCLUSIONS Elevated serum S100B and NSE levels in pediatric TBI patients decreased 1 week after traumatic events. The serum S100B level 1 week after TBI was related to the severity of brain damage. These results indicated that serum S100B and NSE might play a role in predicting the prognosis and monitoring ongoing brain injury in pediatric TBI patients.
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Affiliation(s)
- Dae-Won Park
- Department of Neurosurgery, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, South Korea
| | - Seong-Hyun Park
- Department of Neurosurgery, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, South Korea.
| | - Sung-Kyoo Hwang
- Department of Neurosurgery, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, South Korea
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17
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Singla A, Leineweber B, Monteith S, Oskouian RJ, Tubbs RS. The anatomy of concussion and chronic traumatic encephalopathy: A comprehensive review. Clin Anat 2018; 32:310-318. [DOI: 10.1002/ca.23313] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 11/09/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Amit Singla
- Swedish Neuroscience Institute; Seattle Washington
| | | | | | | | - R. Shane Tubbs
- Seattle Science Foundation; Seattle Washington
- Department of Anatomical Sciences; St. Georges University; St. Georges Grenada
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18
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Golden N, Mahadewa TGB, Aryanti C, Widyadharma IPE. S100B Serum Level as a Mortality Predictor for Traumatic Brain Injury: A Meta-Analysis. Open Access Maced J Med Sci 2018; 6:2239-2244. [PMID: 30559895 PMCID: PMC6290435 DOI: 10.3889/oamjms.2018.432] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/21/2018] [Accepted: 10/22/2018] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND: The pathogenesis of inflammatory neuronal cell damage will continue after traumatic brain injury in which contributed to subsequent mortality. Serum S100B levels were shown to be an early predictor of mortality due to traumatic brain injury. AIM: This Meta-Analysis will analyse the mean and diagnostic strength of serum S100B levels between survived and died subjects with head injuries based on the various follow-up times of nine studies. METHODS: We conducted a meta-anelysis in accordance with PRISMA guidelines and adhering to Cochrane Handbook for Systematic Review of Interventions. Literature search was conducted on March 16, 2018 from Medline and Scopus in the past 10 years, using various keywords related to S100, brain injury, and outcome. Duplicate journals were sorted out via EndNote. Included articles were as follows: original data from the group, clinical trials, case series, patients undergoing serum S100B levels with both short- and long-term follow-up mortality. Data were collected for mortality, serum S100B levels, and its diagnostic strength. All data were analyzed using Review Manager 5.3 (Cochrane, Denmark). RESULTS: The results of the meta-analysis showed a significant difference in S100B levels between survived and died subjects with head injuries on overall follow-up timeline (0.91, 95.9% CI 0.7-1.12, I2 = 98%, p < 0.001), during treatment (1.43, 95% CI 0.97 to 1.89, I2 = 98%, p < 0.001), or 6 months (0.19; 95%CI 0.1-0.29, I2 = 76%, p < 0.001) with an average threshold value that varies according to the study method used. The mean diagnostic strength was also promising to predict early mortality (sensitivity of 77.18% and 92.33%, specificity of 78.35% and 50.6%, respectively). CONCLUSION: S100B serum levels in the future will be potential biomarkers, and it is expected that there will be standardised guidelines for their application.
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Affiliation(s)
- Nyoman Golden
- Department of Neurosurgery, Faculty of Medicine, Udayana University, Sanglah General Hospital, Bali, Indonesia
| | - Tjokorda Gde Bagus Mahadewa
- Department of Neurosurgery, Faculty of Medicine, Udayana University, Sanglah General Hospital, Bali, Indonesia
| | - Citra Aryanti
- Department of Neurosurgery, Faculty of Medicine, Udayana University, Sanglah General Hospital, Bali, Indonesia
| | - I Putu Eka Widyadharma
- Department of Neurology, Faculty of Medicine, Udayana University, Sanglah General Hospital, Bali, Indonesia
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19
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Park SH, Hwang SK. Prognostic Value of Serum Levels of S100 Calcium-Binding Protein B, Neuron-Specific Enolase, and Interleukin-6 in Pediatric Patients with Traumatic Brain Injury. World Neurosurg 2018; 118:e534-e542. [PMID: 30257306 DOI: 10.1016/j.wneu.2018.06.234] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 10/28/2022]
Abstract
OBJECTIVE To analyze serum levels of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), and interleukin (IL)-6 in pediatric patients with traumatic brain injury (TBI) and to assess their relationship with clinical outcome. METHODS To measure biomarkers, peripheral venous blood was collected within 6 hours and 1 week after TBI. Initial Glasgow Coma Scale (GCS) scores and Glasgow Outcome Scale scores 6 months after the trauma were used to evaluate clinical outcome. RESULTS Median serum levels of S100B (178.12 pg/mL), NSE (16.54 ng/mL), and IL-6 (15.48 pg/mL) at admission decreased significantly 1 week after TBI to 40.86 pg/mL, 5.85 ng/mL, and 8.63 pg/mL. In the group with poor GCS scores, serum S100B and NSE levels both at admission and 1 week after TBI were significantly higher than levels in the group with good GCS scores. Serum S100B and NSE levels 1 week after injury in patients with unfavorable 6-month outcomes were significantly higher than levels 1 week after injury in patients with favorable outcomes. CONCLUSIONS Serum levels of S100B, NSE, and IL-6 decreased 1 week after injury. Serum levels of S100B and NSE at admission were related to initial GCS scores, and these levels 1 week after TBI were related to 6-month Glasgow Outcome Scale scores. Thus, serial measurements of serum S100B and NSE, but not IL-6, may help assess brain damage and clinical outcome of pediatric patients with TBI.
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Affiliation(s)
- Seong-Hyun Park
- Department of Neurosurgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.
| | - Sung-Kyoo Hwang
- Department of Neurosurgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
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20
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Grandpierre RG, Bobbia X, de La Coussaye JE, Claret PG. Intérêt clinique des concentrations sériques de la protéine S100β dans l’évaluation des patients traumatisés crâniens. ANNALES FRANCAISES DE MEDECINE D URGENCE 2018. [DOI: 10.3166/afmu-2018-0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Les recommandations de la Société française de médecine d’urgence concernant la prise en charge des patients traumatisés crâniens légers ont été éditées en 2012, complétées par des recommandations sur la bonne utilisation du biomarqueur S100β deux ans plus tard. Grâce à son excellente valeur prédictive négative, la protéine S100β utilisée à travers des règles strictes de prescription a été définie comme une alternative solide à la tomodensitométrie. Cependant, plusieurs questions restent en suspens concernant le délai maximum de réalisation du prélèvement par rapport à l’heure du traumatisme, l’impact médicoéconomique, les variations en rapport avec l’âge du patient, l’impact des agents anticoagulants ou antiagrégants plaquettaires et l’utilité du dosage sérique de cette protéine dans d’autres cadres nosologiques.
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21
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Abu Hamdeh S, Shevchenko G, Mi J, Musunuri S, Bergquist J, Marklund N. Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue. Sci Rep 2018; 8:6807. [PMID: 29717219 PMCID: PMC5931620 DOI: 10.1038/s41598-018-25060-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 04/09/2018] [Indexed: 02/06/2023] Open
Abstract
The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI.
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Affiliation(s)
- Sami Abu Hamdeh
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Ganna Shevchenko
- Analytical Chemistry, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden
| | - Jia Mi
- Analytical Chemistry, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.,Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, China
| | - Sravani Musunuri
- Analytical Chemistry, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden
| | - Jonas Bergquist
- Analytical Chemistry, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.,Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai, China
| | - Niklas Marklund
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden.
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22
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Li M, Sirko S. Traumatic Brain Injury: At the Crossroads of Neuropathology and Common Metabolic Endocrinopathies. J Clin Med 2018. [PMID: 29538298 PMCID: PMC5867585 DOI: 10.3390/jcm7030059] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Building on the seminal work by Geoffrey Harris in the 1970s, the neuroendocrinology field, having undergone spectacular growth, has endeavored to understand the mechanisms of hormonal connectivity between the brain and the rest of the body. Given the fundamental role of the brain in the orchestration of endocrine processes through interactions among neurohormones, it is thus not surprising that the structural and/or functional alterations following traumatic brain injury (TBI) can lead to endocrine changes affecting the whole organism. Taking into account that systemic hormones also act on the brain, modifying its structure and biochemistry, and can acutely and chronically affect several neurophysiological endpoints, the question is to what extent preexisting endocrine dysfunction may set the stage for an adverse outcome after TBI. In this review, we provide an overview of some aspects of three common metabolic endocrinopathies, e.g., diabetes mellitus, obesity, and thyroid dysfunction, and how these could be triggered by TBI. In addition, we discuss how the complex endocrine networks are woven into the responses to sudden changes after TBI, as well as some of the potential mechanisms that, separately or synergistically, can influence outcomes after TBI.
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Affiliation(s)
- Melanie Li
- Physiological Genomics, Biomedical Center (BMC), Institute of Physiology, Medical Faculty of the Ludwig-Maximilian University Munich, 82152 Planegg-Martinsried, Germany.
| | - Swetlana Sirko
- Physiological Genomics, Biomedical Center (BMC), Institute of Physiology, Medical Faculty of the Ludwig-Maximilian University Munich, 82152 Planegg-Martinsried, Germany.
- Institute of Stem Cell Research, Helmholtz Center Munich, Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany.
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23
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Sieber M, Dreßler J, Franke H, Pohlers D, Ondruschka B. Post-mortem biochemistry of NSE and S100B: A supplemental tool for detecting a lethal traumatic brain injury? J Forensic Leg Med 2018; 55:65-73. [PMID: 29471249 DOI: 10.1016/j.jflm.2018.02.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 02/07/2018] [Accepted: 02/11/2018] [Indexed: 12/22/2022]
Abstract
PURPOSE Traumatic brain injury (TBI) is a very common entity that leads to numerous fatalities all over the world. Therefore, forensic pathologists are in desperate need of supplemental methodological tools for the diagnosis of TBI in everyday practice besides the standard autopsy. The present study determined post-mortem neuron specific enolase (NSE) and S100 calcium-binding protein B (S100B) levels as biological markers of an underlying TBI in autopsy cases. METHODS Paired serum and CSF samples of 92 fatalities were collected throughout routine autopsies. Afterwards, the marker levels were assessed using commercially available immunoassays (ECLIA, Roche Diagnostics). For statistical analysis, we compared the TBI cases to three control groups (sudden natural death by acute myocardial infarction, traumatic death without impact on the head, cerebral hypoxia). Moreover, the TBI cases were subdivided according to their survival time of the trauma. Brain specimens have been collected and stained immunohistochemically against the aforementioned proteins to illustrate their typical cellular staining patterns with an underlying TBI compared to non-TBI fatalities. PRINCIPAL RESULTS CSF NSE and S100B levels were elevated after TBI compared to all control groups (p < 0.001). Although this finding can already be investigated among the TBI cases dying immediately subsequent to the trauma, the marker levels in CSF increase with longer survival times until a peak level within the first three days after trauma. There is a strong correlation between both marker levels in CSF (r = 0.67). The presence or absence of cerebral tissue contusion following the initial trauma does not seem to affect the CSF levels of both proteins (p > 0.05). Post-mortem serum levels of both proteins were not elevated in TBI cases compared to controls (p > 0.05). Former elaborated cut-off values in CSF were confirmed and were only exceeded when a TBI survival time of at least 30 min was reached. MAJOR CONCLUSIONS The present results report that post-mortem NSE and S100B CSF levels are significantly elevated subsequent to a fatal TBI.
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Affiliation(s)
- Monique Sieber
- Institute of Legal Medicine, University of Leipzig, Leipzig, Germany
| | - Jan Dreßler
- Institute of Legal Medicine, University of Leipzig, Leipzig, Germany
| | - Heike Franke
- Rudolf Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany
| | - Dirk Pohlers
- Center of Diagnostics GmbH, Klinikum Chemnitz, Chemnitz, Germany
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24
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Bradley-Whitman MA, Roberts KN, Abner EL, Scheff SW, Lynn BC, Lovell MA. A novel method for the rapid detection of post-translationally modified visinin-like protein 1 in rat models of brain injury. Brain Inj 2017; 32:363-380. [PMID: 29283288 DOI: 10.1080/02699052.2017.1418907] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Although elevated serum levels of visinin-like protein 1 (VILIP-1), a neuron-specific calcium sensor protein, are associated with ischaemic stroke, only a single study has evaluated VILIP-1 as a biomarker of traumatic brain injury (TBI). The current proof-of-concept study was designed to determine whether serum VILIP-1 levels increase post-injury in a well-characterized rat unilateral cortical contusion model. METHODS Lateral flow devices (LFDs) rapidly (< 20 min) detected trace serum levels (pg/mL) of VILIP-1 in a small input sample volume (10 µL). Temporal profiles of serum levels at baseline and post-injury were measured in male Sprague Dawley rats subjected to very mild-, mild unilateral-cortical contusion, or naïve surgery and in male Sprague Dawley rats following a diffuse TBI or sham surgery. RESULTS Mean serum levels were significantly elevated by 0.5 h post-injury and remained so throughout the temporal profile compared with baseline in very mild and mild unilateral contusions but not in naïve surgeries. Serum levels were also elevated in a small cohort of animals subjected to a diffuse TBI injury. CONCLUSIONS Overall, the current study demonstrates that the novel LFD is a reliable and rapid point-of-care diagnostic for the detection and quantification of serum levels of UB-VILIP-1 in a clinically relevant time frame.
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Affiliation(s)
| | - Kelly N Roberts
- b Spinal Cord and Brain Injury Research Center , Lexington , KY , USA
| | - Erin L Abner
- c Sanders-Brown Center on Aging & Department of Epidemiology, College of Public Health , University of Kentucky , Lexington , KY , USA
| | - Stephen W Scheff
- d Sanders-Brown Center on Aging & Department of Anatomy and Neurobiology , University of Kentucky , Lexington , KY , USA
| | - Bert C Lynn
- e Sanders-Brown Center on Aging, University of Kentucky Mass Spectrometry, Facility, & Department of Chemistry , University of Kentucky , Lexington , KY , USA
| | - Mark A Lovell
- f Sanders-Brown Center on Aging & Department of Chemistry , University of Kentucky , Lexington , KY , USA
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25
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Mercier E, Tardif PA, Cameron PA, Émond M, Moore L, Mitra B, Ouellet MC, Frenette J, de Guise E, Le Sage N. Prognostic value of neuron-specific enolase (NSE) for prediction of post-concussion symptoms following a mild traumatic brain injury: a systematic review. Brain Inj 2017; 32:29-40. [PMID: 29157007 DOI: 10.1080/02699052.2017.1385097] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND This systematic review aimed to determine the prognostic value of neuron-specific enolase (NSE) to predict post-concussion symptoms following mild traumatic brain injury (TBI). METHODS Seven databases were searched for studies evaluating the association between NSE levels and post-concussion symptoms assessed ≥ 3 months (persistent) or ≥ 7 days < 3 months (early) after mild TBI. Two researchers independently screened studies for inclusion, extracted data and appraised quality using the Quality in Prognostic Studies (QUIPS) tool. RESULTS The search strategy yielded a total of 23,298 citations from which 8 cohorts presented in 10 studies were included. Studies included between 45 and 141 patients (total 608 patients). The outcomes most frequently assessed were post-concussion syndrome (PCS, 12 assessments) and neuropsychological performance deficits (10 assessments). No association was found between an elevated NSE serum level and PCS. Only one study reported a statistically significant association between a higher NSE serum level and alteration of at least three cognitive domains at 2 weeks but this association was no longer significant at 6 weeks. Overall, risk of bias of the included studies was considered moderate. CONCLUSIONS Early NSE serum level is not a strong independent predictor of post-concussion symptoms following mild TBI.
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Affiliation(s)
- Eric Mercier
- a Département de Médecine Familiale et Médecine d'Urgence, Faculté de Médecine , Université Laval , Québec , Canada.,b Axe Santé des Populations et Pratiques Optimales en Santé, Unité de recherche en Traumatologie - Urgence - Soins Intensifs, Centre de recherche du CHU de Québec , Université Laval , Québec , Canada.,c Emergency and Trauma Centre , The Alfred Hospital, Alfred Health , Melbourne , Australia.,d School of Public Health and Preventive Medicine , Monash University , Melbourne , Australia
| | - Pier-Alexandre Tardif
- b Axe Santé des Populations et Pratiques Optimales en Santé, Unité de recherche en Traumatologie - Urgence - Soins Intensifs, Centre de recherche du CHU de Québec , Université Laval , Québec , Canada
| | - Peter A Cameron
- c Emergency and Trauma Centre , The Alfred Hospital, Alfred Health , Melbourne , Australia.,d School of Public Health and Preventive Medicine , Monash University , Melbourne , Australia.,e National Trauma Research Institute , The Alfred Hospital , Melbourne , VIC , Australia
| | - Marcel Émond
- a Département de Médecine Familiale et Médecine d'Urgence, Faculté de Médecine , Université Laval , Québec , Canada.,b Axe Santé des Populations et Pratiques Optimales en Santé, Unité de recherche en Traumatologie - Urgence - Soins Intensifs, Centre de recherche du CHU de Québec , Université Laval , Québec , Canada.,f Axe Santé des Populations et Pratiques Optimales en Santé, Unité de recherche en Vieillissement, Centre de recherche du CHU de Québec , Université Laval , Québec , Canada
| | - Lynne Moore
- b Axe Santé des Populations et Pratiques Optimales en Santé, Unité de recherche en Traumatologie - Urgence - Soins Intensifs, Centre de recherche du CHU de Québec , Université Laval , Québec , Canada.,g Département de Médecine Sociale et Préventive, Faculté de Médecine , Université Laval , Québec , Canada
| | - Biswadev Mitra
- c Emergency and Trauma Centre , The Alfred Hospital, Alfred Health , Melbourne , Australia.,d School of Public Health and Preventive Medicine , Monash University , Melbourne , Australia.,e National Trauma Research Institute , The Alfred Hospital , Melbourne , VIC , Australia
| | - Marie-Christine Ouellet
- b Axe Santé des Populations et Pratiques Optimales en Santé, Unité de recherche en Traumatologie - Urgence - Soins Intensifs, Centre de recherche du CHU de Québec , Université Laval , Québec , Canada.,h Centre Interdisciplinaire de Recherche en Réadaptation et Intégration Sociale (CIRRIS) , Québec , Québec , Canada
| | - Jérôme Frenette
- h Centre Interdisciplinaire de Recherche en Réadaptation et Intégration Sociale (CIRRIS) , Québec , Québec , Canada
| | - Elaine de Guise
- i Research-Institute , McGill University Health Centre , Montreal , Québec , Canada.,j Centre de recherche interdisciplinaire en réadaptation du Montréal métropolitain (CRIR) , Montréal , Québec , Canada
| | - Natalie Le Sage
- a Département de Médecine Familiale et Médecine d'Urgence, Faculté de Médecine , Université Laval , Québec , Canada.,b Axe Santé des Populations et Pratiques Optimales en Santé, Unité de recherche en Traumatologie - Urgence - Soins Intensifs, Centre de recherche du CHU de Québec , Université Laval , Québec , Canada
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26
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Tsitsopoulos PP, Abu Hamdeh S, Marklund N. Current Opportunities for Clinical Monitoring of Axonal Pathology in Traumatic Brain Injury. Front Neurol 2017; 8:599. [PMID: 29209266 PMCID: PMC5702013 DOI: 10.3389/fneur.2017.00599] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 10/25/2017] [Indexed: 01/14/2023] Open
Abstract
Traumatic brain injury (TBI) is a multidimensional and highly complex disease commonly resulting in widespread injury to axons, due to rapid inertial acceleration/deceleration forces transmitted to the brain during impact. Axonal injury leads to brain network dysfunction, significantly contributing to cognitive and functional impairments frequently observed in TBI survivors. Diffuse axonal injury (DAI) is a clinical entity suggested by impaired level of consciousness and coma on clinical examination and characterized by widespread injury to the hemispheric white matter tracts, the corpus callosum and the brain stem. The clinical course of DAI is commonly unpredictable and it remains a challenging entity with limited therapeutic options, to date. Although axonal integrity may be disrupted at impact, the majority of axonal pathology evolves over time, resulting from delayed activation of complex intracellular biochemical cascades. Activation of these secondary biochemical pathways may lead to axonal transection, named secondary axotomy, and be responsible for the clinical decline of DAI patients. Advances in the neurocritical care of TBI patients have been achieved by refinements in multimodality monitoring for prevention and early detection of secondary injury factors, which can be applied also to DAI. There is an emerging role for biomarkers in blood, cerebrospinal fluid, and interstitial fluid using microdialysis in the evaluation of axonal injury in TBI. These biomarker studies have assessed various axonal and neuroglial markers as well as inflammatory mediators, such as cytokines and chemokines. Moreover, modern neuroimaging can detect subtle or overt DAI/white matter changes in diffuse TBI patients across all injury severities using magnetic resonance spectroscopy, diffusion tensor imaging, and positron emission tomography. Importantly, serial neuroimaging studies provide evidence for evolving axonal injury. Since axonal injury may be a key risk factor for neurodegeneration and dementias at long-term following TBI, the secondary injury processes may require prolonged monitoring. The aim of the present review is to summarize the clinical short- and long-term monitoring possibilities of axonal injury in TBI. Increased knowledge of the underlying pathophysiology achieved by advanced clinical monitoring raises hope for the development of novel treatment strategies for axonal injury in TBI.
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Affiliation(s)
- Parmenion P Tsitsopoulos
- Section of Neurosurgery, Department of Neuroscience, Uppsala University, Uppsala, Sweden.,Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece
| | - Sami Abu Hamdeh
- Section of Neurosurgery, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Niklas Marklund
- Section of Neurosurgery, Department of Neuroscience, Uppsala University, Uppsala, Sweden.,Department of Clinical Sciences Lund, Neurosurgery, Skåne University Hospital, Lund University, Lund, Sweden
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27
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Kojima D, Nakamura T, Banno M, Umemoto Y, Kinoshita T, Ishida Y, Tajima F. Head-out immersion in hot water increases serum BDNF in healthy males. Int J Hyperthermia 2017; 34:834-839. [PMID: 29157042 DOI: 10.1080/02656736.2017.1394502] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
PURPOSE Brain-derived neurotrophic factor (BDNF) is an important neurotrophin. The present study investigated the effects of head-out water immersion (HOI) on serum BDNF concentrations. METHODS Eight healthy men performed 20 min head-out water immersion at 42 °C (hot-HOI) and 35 °C (neutral-HOI). These experimental trials were administered in a randomised order separated by at least 7 days. Venous blood samples were withdrawn at rest, immediately after the 20-min HOI, as well as at 15 and 30 min after the end of the HOI. Serum BDNF and S100β, plasma cortisol, platelet and monocyte counts, and core body temperature (Tcb) were measured. RESULTS Tcb was higher at the end of the hot-HOI and 15 min after hot-HOI (p < 0.01), but recovered to pre-HOI level at 30 min after hot-HOI. No change in Tcb was recorded during neutral-HOI. BDNF level was higher (p < 0.05) at the end of the hot-HOI and at 15 min after the end of hot-HOI, and returned to the baseline at 30 min after hot-HOI. S100β, platelet count and monocyte count remained stable throughout the study. Cortisol level was lower at the end of the hot-HOI and returned to pre-HOI level during the recovery period. BDNF and S100β, cortisol, and platelet and monocyte counts did not change throughout the neutral-HOI study. CONCLUSIONS The present findings suggested that the increase in BDNF during 20-min hot-HOI was induced by hyperthermia through enhanced production, rather than by changes in permeability of the blood-brain barrier (BBB), platelet clotting mechanisms or secretion from monocytes.
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Affiliation(s)
- Daisuke Kojima
- a Department of Rehabilitation Medicine, School of Medicine , Wakayama Medical University , Wakayama , Japan
| | - Takeshi Nakamura
- b Department of Rehabilitation Medicine, School of Medicine , Yokohama City University , Yokohama , Kanagawa , Japan
| | - Motohiko Banno
- a Department of Rehabilitation Medicine, School of Medicine , Wakayama Medical University , Wakayama , Japan
| | - Yasunori Umemoto
- a Department of Rehabilitation Medicine, School of Medicine , Wakayama Medical University , Wakayama , Japan
| | - Tokio Kinoshita
- a Department of Rehabilitation Medicine, School of Medicine , Wakayama Medical University , Wakayama , Japan
| | - Yuko Ishida
- c Department of Forensic Medicine, School of Medicine , Wakayama Medical University , Wakayama , Japan
| | - Fumihiro Tajima
- a Department of Rehabilitation Medicine, School of Medicine , Wakayama Medical University , Wakayama , Japan
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Gao X, Zheng P, Kasani S, Wu S, Yang F, Lewis S, Nayeem S, Engler-Chiurazzi EB, Wigginton JG, Simpkins JW, Wu N. Paper-Based Surface-Enhanced Raman Scattering Lateral Flow Strip for Detection of Neuron-Specific Enolase in Blood Plasma. Anal Chem 2017; 89:10104-10110. [PMID: 28817769 DOI: 10.1021/acs.analchem.7b03015] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
An inexpensive and disposable paper-based lateral flow strip (PLFS) has been developed as an immunoassay, in which surface-enhanced Raman scattering (SERS) is utilized for sensing signal transduction. The Au nanostar@Raman Reporter@silica sandwich nanoparticles are developed as the SERS probes, which is the key to the high sensitivity of the device. Compared with a colorimetric PLFS, the SERS-PLFS exhibits superior performance in terms of sensitivity and limit of detection (LOD) in a blood plasma-containing sample matrix. In addition, the SERS-PLFS has been successfully used for detection of neuron-specific enolase (NSE), a traumatic brain injury (TBI) protein biomarker, in diluted blood plasma samples, achieving a LOD of 0.86 ng/mL. Moreover, the SERS-PLFS was successfully employed to measure the NSE level in clinical blood plasma samples taken from deidentified TBI patients. This work demonstrates that the SERS-PLFS has great potential in assisting screening of TBI patients in the point-of-care setting.
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Affiliation(s)
- Xuefei Gao
- Department of Mechanical and Aerospace Engineering, West Virginia University , Morgantown, West Virginia 26506-6106, United States
| | - Peng Zheng
- Department of Mechanical and Aerospace Engineering, West Virginia University , Morgantown, West Virginia 26506-6106, United States
| | - Sujan Kasani
- Lane Department of Computer Science and Electrical Engineering, West Virginia University , Morgantown, West Virginia 26506, United States
| | - Steven Wu
- Department of Mechanical and Aerospace Engineering, West Virginia University , Morgantown, West Virginia 26506-6106, United States
| | - Feng Yang
- Industrial and Management Systems Engineering Department, West Virginia University , Morgantown, West Virginia 26506, United States
| | - Sara Lewis
- Physiology and Pharmacology; Center for Basic and Translational Stroke Research; Center for Neuroscience, Morgantown, West Virginia 26505, United States
| | - Sara Nayeem
- Physiology and Pharmacology; Center for Basic and Translational Stroke Research; Center for Neuroscience, Morgantown, West Virginia 26505, United States
| | - Elizabeth B Engler-Chiurazzi
- Physiology and Pharmacology; Center for Basic and Translational Stroke Research; Center for Neuroscience, Morgantown, West Virginia 26505, United States
| | - Jane G Wigginton
- Department of Surgery, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States
| | - James W Simpkins
- Physiology and Pharmacology; Center for Basic and Translational Stroke Research; Center for Neuroscience, Morgantown, West Virginia 26505, United States
| | - Nianqiang Wu
- Department of Mechanical and Aerospace Engineering, West Virginia University , Morgantown, West Virginia 26506-6106, United States
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Thelin EP, Zeiler FA, Ercole A, Mondello S, Büki A, Bellander BM, Helmy A, Menon DK, Nelson DW. Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review. Front Neurol 2017; 8:300. [PMID: 28717351 PMCID: PMC5494601 DOI: 10.3389/fneur.2017.00300] [Citation(s) in RCA: 172] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Accepted: 06/12/2017] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term "effective half-life" (t1/2) in order to describe the "fall" rate in serum. MATERIALS AND METHODS Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations. RESULTS Following screening (10,389 papers), n = 122 papers were included. The proteins S100B (n = 66) and NSE (n = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1-2 h) though possibly of non-cerebral origin. In contrast, the t1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP (n = 18) appears to have t1/2 of about 24-48 h in severe TBI. The protein UCH-L1 (n = 9) presents a t1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use. CONCLUSION Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI.
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Affiliation(s)
- Eric Peter Thelin
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Frederick Adam Zeiler
- Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
- Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Clinician Investigator Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Ari Ercole
- Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - András Büki
- Szentagothai Research Centre, University of Pecs, Pecs, Hungary
- Department of Neurosurgery, University of Pecs, Pecs, Hungary
- MTA-PTE Clinical Neuroscience MR Research Group, Pecs, Hungary
| | | | - Adel Helmy
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - David K. Menon
- Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
- Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - David W. Nelson
- Section of Perioperative Medicine and Intensive Care, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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Sahu S, Nag DS, Swain A, Samaddar DP. Biochemical changes in the injured brain. World J Biol Chem 2017; 8:21-31. [PMID: 28289516 PMCID: PMC5329711 DOI: 10.4331/wjbc.v8.i1.21] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/23/2016] [Accepted: 12/13/2016] [Indexed: 02/05/2023] Open
Abstract
Brain metabolism is an energy intensive phenomenon involving a wide spectrum of chemical intermediaries. Various injury states have a detrimental effect on the biochemical processes involved in the homeostatic and electrophysiological properties of the brain. The biochemical markers of brain injury are a recent addition in the armamentarium of neuro-clinicians and are being increasingly used in the routine management of neuro-pathological entities such as traumatic brain injury, stroke, subarachnoid haemorrhage and intracranial space occupying lesions. These markers are increasingly being used in assessing severity as well as in predicting the prognostic course of neuro-pathological lesions. S-100 protein, neuron specific enolase, creatinine phosphokinase isoenzyme BB and myelin basic protein are some of the biochemical markers which have been proven to have prognostic and clinical value in the brain injury. While S-100, glial fibrillary acidic protein and ubiquitin C terminal hydrolase are early biomarkers of neuronal injury and have the potential to aid in clinical decision-making in the initial management of patients presenting with an acute neuronal crisis, the other biomarkers are of value in predicting long-term complications and prognosis in such patients. In recent times cerebral microdialysis has established itself as a novel way of monitoring brain tissue biochemical metabolites such as glucose, lactate, pyruvate, glutamate and glycerol while small non-coding RNAs have presented themselves as potential markers of brain injury for future.
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Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir (Wien) 2017; 159:209-225. [PMID: 27957604 PMCID: PMC5241347 DOI: 10.1007/s00701-016-3046-3] [Citation(s) in RCA: 187] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 11/28/2016] [Indexed: 12/12/2022]
Abstract
Background In order to improve injury assessment of brain injuries, protein markers of pathophysiological processes and tissue fate have been introduced in the clinic. The most studied protein “biomarker” of cerebral damage in traumatic brain injury (TBI) is the protein S100B. The aim of this narrative review is to thoroughly analyze the properties and capabilities of this biomarker with focus on clinical utility in the assessment of patients suffering from TBI. Results S100B has successfully been implemented in the clinic regionally (1) to screen mild TBI patients evaluating the need to perform a head computerized tomography, (2) to predict outcome in moderate-to-severe TBI patients, (3) to detect secondary injury development in brain-injured patients and (4) to evaluate treatment efficacy. The potential opportunities and pitfalls of S100B in the different areas usually refer to its specificity and sensitivity to detect and assess intracranial injury. Conclusion Given some shortcomings that should be realized, S100B can be used as a versatile screening, monitoring and prediction tool in the management of TBI patients.
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Affiliation(s)
- Eric Peter Thelin
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
- Neurosurgical Research Laboratory, Karolinska University Hospital, Building R2:02, S-171 76, Stockholm, Sweden.
| | - David W Nelson
- Division of Perioperative Medicine and Intensive Care (PMI), Section Neuro, Karolinska University Hospital, Stockholm, Sweden
- Department of Physiology and Pharmacology, Section of Anesthesiology and Intensive Care, Karolinska Institutet, Stockholm, Sweden
| | - Bo-Michael Bellander
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
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Lee HH, Lee WH, Seo HG, Han D, Kim Y, Oh BM. Current State and Prospects of Development of Blood-based Biomarkers for Mild Traumatic Brain Injury. BRAIN & NEUROREHABILITATION 2017. [DOI: 10.12786/bn.2017.10.e3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Affiliation(s)
- Hyun Haeng Lee
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Woo Hyung Lee
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Han Gil Seo
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Dohyun Han
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Youngsoo Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Korea
| | - Byung-Mo Oh
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
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Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir (Wien) 2017; 159. [PMID: 27957604 PMCID: PMC5241347 DOI: 10.1007/s00701-016-3046-3;] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND In order to improve injury assessment of brain injuries, protein markers of pathophysiological processes and tissue fate have been introduced in the clinic. The most studied protein "biomarker" of cerebral damage in traumatic brain injury (TBI) is the protein S100B. The aim of this narrative review is to thoroughly analyze the properties and capabilities of this biomarker with focus on clinical utility in the assessment of patients suffering from TBI. RESULTS S100B has successfully been implemented in the clinic regionally (1) to screen mild TBI patients evaluating the need to perform a head computerized tomography, (2) to predict outcome in moderate-to-severe TBI patients, (3) to detect secondary injury development in brain-injured patients and (4) to evaluate treatment efficacy. The potential opportunities and pitfalls of S100B in the different areas usually refer to its specificity and sensitivity to detect and assess intracranial injury. CONCLUSION Given some shortcomings that should be realized, S100B can be used as a versatile screening, monitoring and prediction tool in the management of TBI patients.
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Affiliation(s)
- Eric Peter Thelin
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
- Neurosurgical Research Laboratory, Karolinska University Hospital, Building R2:02, S-171 76, Stockholm, Sweden.
| | - David W Nelson
- Division of Perioperative Medicine and Intensive Care (PMI), Section Neuro, Karolinska University Hospital, Stockholm, Sweden
- Department of Physiology and Pharmacology, Section of Anesthesiology and Intensive Care, Karolinska Institutet, Stockholm, Sweden
| | - Bo-Michael Bellander
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
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Biomarkers of Traumatic Brain Injury: Temporal Changes in Body Fluids. eNeuro 2016; 3:eN-REV-0294-16. [PMID: 28032118 PMCID: PMC5175263 DOI: 10.1523/eneuro.0294-16.2016] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/17/2016] [Accepted: 11/28/2016] [Indexed: 12/31/2022] Open
Abstract
Traumatic brain injuries (TBIs) are caused by a hit to the head or a sudden acceleration/deceleration movement of the head. Mild TBIs (mTBIs) and concussions are difficult to diagnose. Imaging techniques often fail to find alterations in the brain, and computed tomography exposes the patient to radiation. Brain-specific biomolecules that are released upon cellular damage serve as another means of diagnosing TBI and assessing the severity of injury. These biomarkers can be detected from samples of body fluids using laboratory tests. Dozens of TBI biomarkers have been studied, and research related to them is increasing. We reviewed the recent literature and selected 12 biomarkers relevant to rapid and accurate diagnostics of TBI for further evaluation. The objective was especially to get a view of the temporal profiles of the biomarkers’ rise and decline after a TBI event. Most biomarkers are rapidly elevated after injury, and they serve as diagnostics tools for some days. Some biomarkers are elevated for months after injury, although the literature on long-term biomarkers is scarce. Clinical utilization of TBI biomarkers is still at a very early phase despite years of active research.
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Young GB. WITHDRAWN: The unresponsive-wakefulness syndrome: A seismic shift in etiology? Resuscitation 2016:S0300-9572(16)30462-2. [PMID: 27645311 DOI: 10.1016/j.resuscitation.2016.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 09/09/2016] [Indexed: 11/25/2022]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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Affiliation(s)
- G Bryan Young
- Departments of Clinical Neurological Sciences and Medicine (Critical Care), Western University, London, Ontario, Canada.
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Graham EM, Burd I, Everett AD, Northington FJ. Blood Biomarkers for Evaluation of Perinatal Encephalopathy. Front Pharmacol 2016; 7:196. [PMID: 27468268 PMCID: PMC4942457 DOI: 10.3389/fphar.2016.00196] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 06/20/2016] [Indexed: 12/17/2022] Open
Abstract
Recent research in identification of brain injury after trauma shows many possible blood biomarkers that may help identify the fetus and neonate with encephalopathy. Traumatic brain injury shares many common features with perinatal hypoxic-ischemic encephalopathy. Trauma has a hypoxic component, and one of the 1st physiologic consequences of moderate-severe traumatic brain injury is apnea. Trauma and hypoxia-ischemia initiate an excitotoxic cascade and free radical injury followed by the inflammatory cascade, producing injury in neurons, glial cells and white matter. Increased excitatory amino acids, lipid peroxidation products, and alteration in microRNAs and inflammatory markers are common to both traumatic brain injury and perinatal encephalopathy. The blood-brain barrier is disrupted in both leading to egress of substances normally only found in the central nervous system. Brain exosomes may represent ideal biomarker containers, as RNA and protein transported within the vesicles are protected from enzymatic degradation. Evaluation of fetal or neonatal brain derived exosomes that cross the blood-brain barrier and circulate peripherally has been referred to as the "liquid brain biopsy." A multiplex of serum biomarkers could improve upon the current imprecise methods of identifying fetal and neonatal brain injury such as fetal heart rate abnormalities, meconium, cord gases at delivery, and Apgar scores. Quantitative biomarker measurements of perinatal brain injury and recovery could lead to operative delivery only in the presence of significant fetal risk, triage to appropriate therapy after birth and measure the effectiveness of treatment.
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Affiliation(s)
- Ernest M. Graham
- Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of MedicineBaltimore, MD, USA
- Neuroscience Intensive Care Nursery Program, Johns Hopkins University School of MedicineBaltimore, MD, USA
| | - Irina Burd
- Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of MedicineBaltimore, MD, USA
- Neuroscience Intensive Care Nursery Program, Johns Hopkins University School of MedicineBaltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of MedicineBaltimore, MD, USA
- Integrated Research Center for Fetal Medicine, Johns Hopkins University School of MedicineBaltimore, MD, USA
| | - Allen D. Everett
- Neuroscience Intensive Care Nursery Program, Johns Hopkins University School of MedicineBaltimore, MD, USA
- Division of Cardiology, Department of Pediatrics, Johns Hopkins University School of MedicineBaltimore, MD, USA
| | - Frances J. Northington
- Neuroscience Intensive Care Nursery Program, Johns Hopkins University School of MedicineBaltimore, MD, USA
- Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of MedicineBaltimore, MD, USA
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Ercole A, Thelin EP, Holst A, Bellander BM, Nelson DW. Kinetic modelling of serum S100b after traumatic brain injury. BMC Neurol 2016; 16:93. [PMID: 27315805 PMCID: PMC4912776 DOI: 10.1186/s12883-016-0614-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 06/02/2016] [Indexed: 11/29/2022] Open
Abstract
Background An understanding of the kinetics of a biomarker is essential to its interpretation. Despite this, little kinetic modelling of blood biomarkers can be found in the literature. S100b is an astrocyte related marker of brain injury used primarily in traumatic brain injury (TBI). Serum levels are expected to be the net result of a multi-compartmental process. The optimal sample times for TBI prognostication, and to follow injury development, are unclear. The purpose of this study was to develop a kinetic model to characterise the temporal course of serum S100b concentration after primary traumatic brain injury. Methods Data of serial serum S100b samples from 154 traumatic brain injury patients in a neurointensive care unit were retrospectively analysed, including only patients without secondary peaks of this biomarker. Additionally, extra-cranial S100b can confound samples earlier than 12 h after trauma and were therefore excluded. A hierarchical, Bayesian gamma variate kinetic model was constructed and the parameters estimated by Markov chain Monte Carlo sampling. Results We demonstrated that S100b concentration changes dramatically over timescales that are clinically important for early prognostication with a peak at 27.2 h (95 % credible interval [25.6, 28.8]). Baseline S100b levels was found to be 0.11 μg/L (95 % credible interval [0.10, 0.12]). Conclusions Even small differences in injury to sample time may lead to marked changes in S100b during the first days after injury. This must be taken into account in interpretation. The model offers a way to predict the peak and trajectory of S100b from 12 h post trauma in TBI patients, and to identify deviations from this, possibly indicating a secondary event. Kinetic modelling, providing an equation for the peak and projection, may offer a way to reduce the ambiguity in interpretation of, in time, randomly sampled acute biomarkers and may be generally applicable to biomarkers with, in time, well defined hits.
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Affiliation(s)
- A Ercole
- Division of Anaesthesia, University of Cambridge, Cambridge, UK
| | - E P Thelin
- Section for Neurosurgery, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - A Holst
- School of Computer Science and Communication, KTH Royal Institute of Technology, Stockholm, Sweden
| | - B M Bellander
- Section for Neurosurgery, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - D W Nelson
- Section for Anesthesiology and Intensive Care, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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Thompson WH, Thelin EP, Lilja A, Bellander BM, Fransson P. Functional resting-state fMRI connectivity correlates with serum levels of the S100B protein in the acute phase of traumatic brain injury. Neuroimage Clin 2016; 12:1004-1012. [PMID: 27995066 PMCID: PMC5153599 DOI: 10.1016/j.nicl.2016.05.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Revised: 04/21/2016] [Accepted: 05/05/2016] [Indexed: 12/20/2022]
Abstract
The S100B protein is an intra-cellular calcium-binding protein that mainly resides in astrocytes in the central nervous system. The serum level of S100B is used as biomarker for the severity of brain damage in traumatic brain injury (TBI) patients. In this study we investigated the relationship between intrinsic resting-state brain connectivity, measured 1-22 days (mean 8 days) after trauma, and serum levels of S100B in a patient cohort with mild-to-severe TBI in need of neuro-intensive care in the acute phase. In line with previous investigations, our results show that the peak level of S100B acquired during the acute phase of TBI was negatively correlated with behavioral measures (Glasgow Outcome Score, GOS) of functional outcome assessed 6 to 12 months post injury. Using a multi-variate pattern analysis-informed seed-based correlation analysis, we show that the strength of resting-state brain connectivity in multiple resting-state networks was negatively correlated with the peak of serum levels of S100B. A negative correspondence between S100B peak levels recorded 12-36 h after trauma and intrinsic connectivity was found for brain regions located in the default mode, fronto-parietal, visual and motor resting-state networks. Our results suggest that resting-state brain connectivity measures acquired during the acute phase of TBI is concordant with results obtained from molecular biomarkers and that it may hold a capacity to predict long-term cognitive outcome in TBI patients.
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Affiliation(s)
| | - Eric Peter Thelin
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Anders Lilja
- Section of Neuroradiology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Bo-Michael Bellander
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
| | - Peter Fransson
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Utilidad de los biomarcadores en el pronóstico del traumatismo craneoencefálico grave. Med Intensiva 2016; 40:105-12. [DOI: 10.1016/j.medin.2015.11.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 11/03/2015] [Accepted: 11/18/2015] [Indexed: 11/21/2022]
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Wang KKW, Yang Z, Yue JK, Zhang Z, Winkler EA, Puccio AM, Diaz-Arrastia R, Lingsma HF, Yuh EL, Mukherjee P, Valadka AB, Gordon WA, Okonkwo DO, Manley GT, Cooper SR, Dams-O'Connor K, Hricik AJ, Inoue T, Maas AIR, Menon DK, Schnyer DM, Sinha TK, Vassar MJ. Plasma Anti-Glial Fibrillary Acidic Protein Autoantibody Levels during the Acute and Chronic Phases of Traumatic Brain Injury: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study. J Neurotrauma 2016; 33:1270-7. [PMID: 26560343 DOI: 10.1089/neu.2015.3881] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
We described recently a subacute serum autoantibody response toward glial fibrillary acidic protein (GFAP) and its breakdown products 5-10 days after severe traumatic brain injury (TBI). Here, we expanded our anti-GFAP autoantibody (AutoAb[GFAP]) investigation to the multicenter observational study Transforming Research and Clinical Knowledge in TBI Pilot (TRACK-TBI Pilot) to cover the full spectrum of TBI (Glasgow Coma Scale 3-15) by using acute (<24 h) plasma samples from 196 patients with acute TBI admitted to three Level I trauma centers, and a second cohort of 21 participants with chronic TBI admitted to inpatient TBI rehabilitation. We find that acute patients self-reporting previous TBI with loss of consciousness (LOC) (n = 43) had higher day 1 AutoAb[GFAP] (mean ± standard error: 9.11 ± 1.42; n = 43) than healthy controls (2.90 ± 0.92; n = 16; p = 0.032) and acute patients reporting no previous TBI (2.97 ± 0.37; n = 106; p < 0.001), but not acute patients reporting previous TBI without LOC (8.01 ± 1.80; n = 47; p = 0.906). These data suggest that while exposure to TBI may trigger the AutoAb[GFAP] response, circulating antibodies are elevated specifically in acute TBI patients with a history of TBI. AutoAb[GFAP] levels for participants with chronic TBI (average post-TBI time 176 days or 6.21 months) were also significantly higher (15.08 ± 2.82; n = 21) than healthy controls (p < 0.001). These data suggest a persistent upregulation of the autoimmune response to specific brain antigen(s) in the subacute to chronic phase after TBI, as well as after repeated TBI insults. Hence, AutoAb[GFAP] may be a sensitive assay to study the dynamic interactions between post-injury brain and patient-specific autoimmune responses across acute and chronic settings after TBI.
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Affiliation(s)
- Kevin K W Wang
- 1 Departments of Psychiatry and Neuroscience, University of Florida , Gainesville, Florida
| | - Zhihui Yang
- 1 Departments of Psychiatry and Neuroscience, University of Florida , Gainesville, Florida
| | - John K Yue
- 2 Brain and Spinal Injury Center, San Francisco General Hospital , San Francisco, California.,3 Department of Neurological Surgery, University of California , San Francisco, San Francisco, California
| | - Zhiqun Zhang
- 1 Departments of Psychiatry and Neuroscience, University of Florida , Gainesville, Florida
| | - Ethan A Winkler
- 2 Brain and Spinal Injury Center, San Francisco General Hospital , San Francisco, California.,3 Department of Neurological Surgery, University of California , San Francisco, San Francisco, California
| | - Ava M Puccio
- 4 Department of Neurological Surgery, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania
| | - Ramon Diaz-Arrastia
- 5 Department of Neurology, Uniformed Services University of the Health Sciences , and Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland
| | - Hester F Lingsma
- 6 Department of Public Health, Erasmus Medical Center , Rotterdam, The Netherlands
| | - Esther L Yuh
- 2 Brain and Spinal Injury Center, San Francisco General Hospital , San Francisco, California.,7 Department of Radiology, University of California , San Francisco, San Francisco, California
| | - Pratik Mukherjee
- 2 Brain and Spinal Injury Center, San Francisco General Hospital , San Francisco, California.,7 Department of Radiology, University of California , San Francisco, San Francisco, California
| | | | - Wayne A Gordon
- 9 Department of Rehabilitation Medicine, Mount Sinai School of Medicine , New York, New York
| | - David O Okonkwo
- 4 Department of Neurological Surgery, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania
| | - Geoffrey T Manley
- 2 Brain and Spinal Injury Center, San Francisco General Hospital , San Francisco, California.,3 Department of Neurological Surgery, University of California , San Francisco, San Francisco, California
| | - Shelly R Cooper
- 2 Brain and Spinal Injury Center, San Francisco General Hospital , San Francisco, California.,3 Department of Neurological Surgery, University of California , San Francisco, San Francisco, California.,6 Department of Public Health, Erasmus Medical Center , Rotterdam, The Netherlands
| | - Kristen Dams-O'Connor
- 9 Department of Rehabilitation Medicine, Mount Sinai School of Medicine , New York, New York
| | - Allison J Hricik
- 4 Department of Neurological Surgery, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania
| | - Tomoo Inoue
- 2 Brain and Spinal Injury Center, San Francisco General Hospital , San Francisco, California.,3 Department of Neurological Surgery, University of California , San Francisco, San Francisco, California
| | - Andrew I R Maas
- 10 Department of Neurosurgery, Antwerp University Hospital , Edegem, Belgium
| | - David K Menon
- 11 Division of Anaesthesia, University of Cambridge and Addenbrooke's Hospital , Cambridge, United Kingdom
| | - David M Schnyer
- 12 Department of Psychology, University of Texas , Austin, Texas
| | - Tuhin K Sinha
- 7 Department of Radiology, University of California , San Francisco, San Francisco, California
| | - Mary J Vassar
- 2 Brain and Spinal Injury Center, San Francisco General Hospital , San Francisco, California.,3 Department of Neurological Surgery, University of California , San Francisco, San Francisco, California
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Barateiro A, Afonso V, Santos G, Cerqueira JJ, Brites D, van Horssen J, Fernandes A. S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis. Mol Neurobiol 2015; 53:3976-3991. [DOI: 10.1007/s12035-015-9336-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 07/01/2015] [Indexed: 12/30/2022]
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Schulte S, Podlog LW, Hamson-Utley JJ, Strathmann FG, Strüder HK. A systematic review of the biomarker S100B: implications for sport-related concussion management. J Athl Train 2015; 49:830-50. [PMID: 25299445 DOI: 10.4085/1062-6050-49.3.33] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Elevated levels of the astroglial protein S100B have been shown to predict sport-related concussion. However, S100B levels within an athlete can vary depending on the type of physical activity (PA) engaged in and the methodologic approach used to measure them. Thus, appropriate reference values in the diagnosis of concussed athletes remain undefined. The purpose of our systematic literature review was to provide an overview of the current literature examining S100B measurement in the context of PA. The overall goal is to improve the use of the biomarker S100B in the context of sport-related concussion management. DATA SOURCES PubMed, SciVerse Scopus, SPORTDiscus, CINAHL, and Cochrane. STUDY SELECTION We selected articles that contained (1) research studies focusing exclusively on humans in which (2) either PA was used as an intervention or the test participants or athletes were involved in PA and (3) S100B was measured as a dependent variable. DATA EXTRACTION We identified 24 articles. Study variations included the mode of PA used as an intervention, sample types, sample-processing procedures, and analytic techniques. DATA SYNTHESIS Given the nonuniformity of the analytical methods used and the data samples collected, as well as differences in the types of PA investigated, we were not able to determine a single consistent reference value of S100B in the context of PA. Thus, a clear distinction between a concussed athlete and a healthy athlete based solely on the existing S100B cutoff value of 0.1 μg/L remains unclear. However, because of its high sensitivity and excellent negative predictive value, S100B measurement seems to have the potential to be a diagnostic adjunct for concussion in sports settings. We recommend that the interpretation of S100B values be based on congruent study designs to ensure measurement reliability and validity.
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Affiliation(s)
- Stefanie Schulte
- Department of Exercise and Sport Science, University of Utah, Salt Lake City
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Olivecrona Z, Bobinski L, Koskinen LOD. Association of ICP, CPP, CT findings and S-100B and NSE in severe traumatic head injury. Prognostic value of the biomarkers. Brain Inj 2014; 29:446-54. [PMID: 25518864 DOI: 10.3109/02699052.2014.989403] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE The association was studied of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) on S-100B and neuron-specific enolase (NSE) in severe traumatic brain injury (sTBI). The relationship was explored between biomarkers, ICP, CPP, CT-scan classifications and the clinical outcome. MATERIALS AND METHODS Data were collected prospectively and consecutively in 48 patients with Glasgow Coma Scale score ≤ 8, age 15-70 years. NSE and S-100B were analysed during 5 consecutive days. The initial and follow-up CT-scans were classified according to the Marshall, Rotterdam and Morris-Marshall classifications. Outcome was evaluated with extended Glasgow outcome scale at 3 months. RESULTS Maximal ICP and minimal CPP correlated with S-100B and NSE levels. Complex relations between biomarkers and CT classifications were observed. S-100B bulk release (AUC = 0.8333, p = 0.0009), and NSE at 72 hours (AUC = 0.8476, p = 0.0045) had the highest prediction power of mortality. Combining Morris-Marshall score and S-100B bulk release improved the prediction of clinical outcome (AUC = 0.8929, p = 0.0008). CONCLUSION Biomarker levels are associated with ICP and CPP and reflect different aspects of brain injury as evaluated by CT-scan. The biomarkers might predict mortality. There are several pitfalls influencing the interpretation of biomarker data in respect to ICP, CPP, CT-findings and clinical outcome.
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Affiliation(s)
- Zandra Olivecrona
- Institution of Pharmacology and Clinical Neuroscience, Department of Neurosurgery, Umeå University , Umeå , Sweden
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Abstract
Background:It has been shown previously that S-100β levels in serum correspond with the severity of central nervous system (CNS) trauma. It also has been suggested that S-100β in CNS tissue is involved in neuroprotection and neuroregeneration. We have previously shown that administration of quercetin results in improved motor function in an animal model of spinal cord trauma.Methods:Mid-thoracic spinal cord compression injury was produced in adult maleWistar rats. Serum and tissue samples were acquired from quercetin-treated animals (25 μmol / kg) and saline controls at 6, 12 and 24 hours after the trauma. S-100β levels were measured using a luminometric assay in the damaged tissue and in the serum of the animals.Results:The increase in serum S-100β levels seen in saline controls after spinal cord trauma was ameliorated in the quercetin-treated animals at all time points, although the difference to saline controls became statistically significant only at 24 hrs after the trauma. Compared to tissue S-100β levels in healthy animals, values were significantly decreased in saline controls at all three time points, while they were decreased at 6 hrs and increased at both 12 and 24 hrs in quercetin-treated animals. At all three time points tissue S-100β levels were significantly higher in quercetin-treated animals than in saline controls.Conclusions:Administration of quercetin results in modification of S-100β levels in the setting of experimental spinal cord trauma. The kinetic patterns of the S-100β fluctuations in serum and tissue suggest that post-traumatic administration of quercetin decreases the extent of CNS injury.
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Abstract
Background:As has been shown previously, S-100β levels in serum can be a useful predictor of brain damage after head trauma. This pilot study was designed to investigate whether urine samples, which are much easier to obtain, could be used for the same purpose instead of serum samples.Methods:Ninety-six consecutive patients admitted with head trauma were recruited in the study. After exclusion of 54 patients, mostly because of significant additional trauma, S-100β levels were analyzed in serum and urine of 42 patients using a luminometric assay. A range for normal values was established based on samples from ten healthy volunteers.Results:S-100β serum levels increased proportional to the severity of the head trauma, as had been previously shown by several other groups. In many patients, initial increases in urine S-100β levels were seen later than in serum, after which the kinetics of S-100β levels in urine seemed to follow that established for serum levels. S-100β values in urine were on average about 54% lower in urine than in serum.Conclusions:S-100β levels in urine obtained on admission to the hospital are not a good indicator for the extent of brain damage. However, urine S-100β levels obtained at later time points might be a useful indicator for the development of secondary brain injury.
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Wuthisuthimethawee P, Saeheng S, Oearsakul T. Serum cleaved tau protein and traumatic mild head injury: a preliminary study in the Thai population. Eur J Trauma Emerg Surg 2013; 39:293-6. [PMID: 26815235 DOI: 10.1007/s00068-013-0263-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 02/04/2013] [Indexed: 11/28/2022]
Abstract
PURPOSE To determine the correlation between serum cleaved tau protein and traumatic mild head injury (MHI) (GCS 13-15). METHODS A prospective observational study was conducted. Blood specimens from 12 healthy persons and 44 adult patients with traumatic MHI were collected in the emergency department to measure the cleaved tau protein level using a Human Tau phosphoSerine 396 ELISA kit. A brain computed tomography (CT) scan was done in all patients. The serum cleaved tau protein level was considered positive at a cut-off point of 0.1 pg/ml. An intracranial lesion was defined as any abnormality detected by brain CT scan. RESULTS The mean age of the traumatic MHI patients was 34.9 ± 15.6 years (range 15-74). The median GCS was 15. The median time from injury to arrival at the emergency department was 30 min. There were 11 intracranial lesions detected by brain CT scan (25.0 %). Serum cleaved tau protein was not detected in either healthy or traumatic MHI patients. CONCLUSION As it was uncorrelated with traumatic MHI, serum cleaved tau protein proved to be an unreliable biomarker to use in the early detection of and decision-making for traumatic MHI patients at the emergency department.
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Affiliation(s)
- P Wuthisuthimethawee
- Department of Emergency Medicine, Faculty of Medicine, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand.
| | - S Saeheng
- Department of Surgery, Faculty of Medicine, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand
| | - T Oearsakul
- Department of Surgery, Faculty of Medicine, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand
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Guingab-Cagmat JD, Cagmat EB, Hayes RL, Anagli J. Integration of proteomics, bioinformatics, and systems biology in traumatic brain injury biomarker discovery. Front Neurol 2013; 4:61. [PMID: 23750150 PMCID: PMC3668328 DOI: 10.3389/fneur.2013.00061] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 05/12/2013] [Indexed: 01/18/2023] Open
Abstract
Traumatic brain injury (TBI) is a major medical crisis without any FDA-approved pharmacological therapies that have been demonstrated to improve functional outcomes. It has been argued that discovery of disease-relevant biomarkers might help to guide successful clinical trials for TBI. Major advances in mass spectrometry (MS) have revolutionized the field of proteomic biomarker discovery and facilitated the identification of several candidate markers that are being further evaluated for their efficacy as TBI biomarkers. However, several hurdles have to be overcome even during the discovery phase which is only the first step in the long process of biomarker development. The high-throughput nature of MS-based proteomic experiments generates a massive amount of mass spectral data presenting great challenges in downstream interpretation. Currently, different bioinformatics platforms are available for functional analysis and data mining of MS-generated proteomic data. These tools provide a way to convert data sets to biologically interpretable results and functional outcomes. A strategy that has promise in advancing biomarker development involves the triad of proteomics, bioinformatics, and systems biology. In this review, a brief overview of how bioinformatics and systems biology tools analyze, transform, and interpret complex MS datasets into biologically relevant results is discussed. In addition, challenges and limitations of proteomics, bioinformatics, and systems biology in TBI biomarker discovery are presented. A brief survey of researches that utilized these three overlapping disciplines in TBI biomarker discovery is also presented. Finally, examples of TBI biomarkers and their applications are discussed.
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Yokobori S, Hosein K, Burks S, Sharma I, Gajavelli S, Bullock R. Biomarkers for the clinical differential diagnosis in traumatic brain injury--a systematic review. CNS Neurosci Ther 2013; 19:556-65. [PMID: 23710877 DOI: 10.1111/cns.12127] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 04/17/2013] [Accepted: 04/18/2013] [Indexed: 01/24/2023] Open
Abstract
Rapid triage and decision-making in the treatment of traumatic brain injury (TBI) present challenging dilemma in "resource poor" environments such as the battlefield and developing areas of the world. There is an urgent need for additional tools to guide treatment of TBI. The aim of this review is to establish the possible use of diagnostic TBI biomarkers in (1) identifying diffuse and focal brain injury and (2) assess their potential for determining outcome, intracranial pressure (ICP), and responses to therapy. At present, there is insufficient literature to support a role for diagnostic biomarkers in distinguishing focal and diffuse injury or for accurate determination of raised ICP. Presently, neurofilament (NF), S100β, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1) seemed to have the best potential as diagnostic biomarkers for distinguishing focal and diffuse injury, whereas C-tau, neuron-specific enolase (NSE), S100β, GFAP, and spectrin breakdown products (SBDPs) appear to be candidates for ICP reflective biomarkers. With the combinations of different pathophysiology related to each biomarker, a multibiomarker analysis seems to be effective and would likely increase diagnostic accuracy. There is limited research focusing on the differential diagnostic properties of biomarkers in TBI. This fact warrants the need for greater efforts to innovate sensitive and reliable biomarkers. We advocate awareness and inclusion of the differentiation of injury type and ICP elevation in further studies with brain injury biomarkers.
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Affiliation(s)
- Shoji Yokobori
- Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
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Olivecrona Z, Dahlqvist P, Koskinen LOD. Acute neuro-endocrine profile and prediction of outcome after severe brain injury. Scand J Trauma Resusc Emerg Med 2013; 21:33. [PMID: 23601250 PMCID: PMC3637196 DOI: 10.1186/1757-7241-21-33] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 04/02/2013] [Indexed: 01/24/2023] Open
Abstract
OBJECT The aim of the study was to evaluate the early changes in pituitary hormone levels after severe traumatic brain injury (sTBI) and compare hormone levels to basic neuro-intensive care data, a systematic scoring of the CT-findings and to evaluate whether hormone changes are related to outcome. METHODS Prospective study, including consecutive patients, 15-70 years, with sTBI, Glasgow Coma Scale (GCS) score ≤ 8, initial cerebral perfusion pressure > 10 mm Hg, and arrival to our level one trauma university hospital within 24 hours after head trauma (n = 48). Serum samples were collected in the morning (08-10 am) day 1 and day 4 after sTBI for analysis of cortisol, growth hormone (GH), prolactin, insulin-like growth factor 1 (IGF-1), thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), follicular stimulating hormone (FSH), luteinizing hormone (LH), testosterone and sex hormone-binding globulin (SHBG) (men). Serum for cortisol and GH was also obtained in the evening (17-19 pm) at day 1 and day 4. The first CT of the brain was classified according to Marshall. Independent staff evaluated outcome at 3 months using GOS-E. RESULTS Profound changes were found for most pituitary-dependent hormones in the acute phase after sTBI, i.e. low levels of thyroid hormones, strong suppression of the pituitary-gonadal axis and increased levels of prolactin. The main findings of this study were: 1) A large proportion (54% day 1 and 70% day 4) of the patients showed morning s-cortisol levels below the proposed cut-off levels for critical illness related corticosteroid insufficiency (CIRCI), i.e. <276 nmol/L (=10 ug/dL), 2) Low s-cortisol was not associated with higher mortality or worse outcome at 3 months, 3) There was a significant association between early (day 1) and strong suppression of the pituitary-gonadal axis and improved survival and favorable functional outcome 3 months after sTBI, 4) Significantly lower levels of fT3 and TSH at day 4 in patients with a poor outcome at 3 months. 5) A higher Marshall CT score was associated with higher day 1 LH/FSH- and lower day 4 TSH levels 6) In general no significant correlation between GCS, ICP or CPP and hormone levels were detected. Only ICPmax and LH day 1 in men was significantly correlated. CONCLUSION Profound dynamic changes in hormone levels are found in the acute phase of sTBI. This is consistent with previous findings in different groups of critically ill patients, most of which are likely to be attributed to physiological adaptation to acute illness. Low cortisol levels were a common finding, and not associated with unfavorable outcome. A retained ability to a dynamic hormonal response, i.e. fast and strong suppression of the pituitary-gonadal axis (day 1) and ability to restore activity in the pituitary-thyroid axis (day 4) was associated with less severe injury according to CT-findings and favorable outcome.
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Affiliation(s)
- Zandra Olivecrona
- Department of Pharmacology and Clinical Neuroscience, Division of Neurosurgery, Umeå University, SE 90185, Umeå, Sweden
| | - Per Dahlqvist
- Department of Public Health and Clinical Medicine, Umeå University, SE 90185, Umeå, Sweden
| | - Lars-Owe D Koskinen
- Department of Pharmacology and Clinical Neuroscience, Division of Neurosurgery, Umeå University, SE 90185, Umeå, Sweden
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Thelin EP, Johannesson L, Nelson D, Bellander BM. S100B is an important outcome predictor in traumatic brain injury. J Neurotrauma 2013; 30:519-28. [PMID: 23297751 DOI: 10.1089/neu.2012.2553] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The objective of the study was to examine how S100B, a biomarker of traumatic brain injury (TBI), contributes to outcome prediction after adjusting for known parameters, including age, Glasgow Coma Scale (GCS), pupil reaction, and computed tomography (CT) variables; to examine which parameters have the best correlation to elevated serum levels of S100B; and to investigate when to sample S100B to achieve the strongest association to outcome. This retrospective study included 265 patients with TBI admitted to the neurointensive care unit, Karolinska University Hospital Solna, Stockholm, Sweden. Univariate and multivariate proportional odds regressions were performed to determine parameters most closely related to outcome, and how S100B adds to prediction accuracy. Age (p<0.0001), pupil reaction (p<0.0001), and levels of S100B (p<0.0001) had the strongest statistical correlation to outcome. The area under curve of S100B, the first 48 h after trauma, yielded an additional explained variance of 6.6% in excess of known outcome parameters, including age, GCS, pupil reaction, and CT variables, themselves exhibiting an explained variance of 29.3%. S100B adds substantial information regarding patient outcome, in excess of that provided by known parameters. Only CT variables were found to be significant predictors of increased levels of S100B in uni- and multivariate analysis. Early samples of S100B, within 12 h after trauma, appear to have little prognostic value, and S100B should likely be sampled 12-36 h following trauma to best enhance TBI outcome prediction.
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Affiliation(s)
- Eric Peter Thelin
- Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
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