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Hicks AJ, Carrington H, Bura L, Yang A, Pesce R, Yew B, Dams-O'Connor K. Blood-Based Protein Biomarkers in the Chronic Phase of Traumatic Brain Injury: A Systematic Review. J Neurotrauma 2025; 42:759-797. [PMID: 40176450 DOI: 10.1089/neu.2024.0294] [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] [Indexed: 04/04/2025] Open
Abstract
There has been limited exploration of blood-based biomarkers in the chronic period following traumatic brain injury (TBI). Our objective was to conduct a systematic review of studies examining blood-based protein biomarkers with at least one sample collected 12 months post-TBI in adults (≥16 years). Database searches were conducted in Embase, MEDLINE, and Science Citation Index-Expanded on July 24, 2023. Risk of bias was assessed using modified Joanna Briggs Institute critical appraisal tools. Only 30 of 12,523 articles met inclusion criteria, with samples drawn from 12 months to 48 years. Higher quality evidence (low risk of bias; large samples) identified promising inflammatory biomarkers at 12 months post-injury in both moderate-severe TBI (GFAP) and mild TBI (eotaxin-1, IFN-y, IL-8, IL-9, IL-17A, MCP-1, MIP-1β, FGF-basic, and TNF-α). Studies with low risk of bias but smaller samples also suggest NSE, MME, and CRP may be informative, alongside protein variants for α-syn (10H, D5), amyloid-β (A4, C6T), TDP-43 (AD-TDP 1;2;3;9;11), and tau (D11C). Findings for NfL were inconclusive. Longitudinal data were mostly available for acute samples followed until 12 months post-injury, with limited evaluation of changes beyond 12 months. Associations of some blood-based biomarkers with cognitive, sleep, and functional outcomes were reported. The overall strength of the evidence in this review was limited by the risk of bias and small sample sizes. Replication is required within prospective longitudinal studies that move beyond 12 months post-injury. Novel efforts should be guided by promising neurodegenerative-disease markers and use panels to model polypathology.
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Affiliation(s)
- Amelia J Hicks
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Holly Carrington
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Lisa Bura
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Alicia Yang
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Rico Pesce
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Belinda Yew
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Ionescu C, Ghidersa M, Ciobica A, Mavroudis I, Kazis D, Petridis FE, Gorgan DL, Balmus IM. Potential Correlation Between Molecular Biomarkers and Oxidative Stress in Traumatic Brain Injury. Int J Mol Sci 2025; 26:3858. [PMID: 40332547 PMCID: PMC12027598 DOI: 10.3390/ijms26083858] [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: 03/14/2025] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 05/08/2025] Open
Abstract
Diagnosing traumatic brain injury (TBI) remains challenging due to an incomplete understanding of its neuropathological mechanisms. TBI is recognised as a complex condition involving both primary and secondary injuries. Although oxidative stress is a non-specific molecular phenomenon observed in various neuropathological conditions, it plays a crucial role in brain injury response and recovery. Due to these aspects, we aimed to evaluate the interaction between some known TBI molecular biomarkers and oxidative stress in providing evidence for its possible relevance in clinical diagnosis and outcome prediction. We found that while many of the currently validated molecular biomarkers interact with oxidative pathways, their patterns of variation could assist the diagnosis, prognosis, and outcomes prediction in TBI cases.
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Affiliation(s)
- Cătălina Ionescu
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, 700505 Iasi, Romania; (C.I.); (M.G.); (A.C.); (D.L.G.)
| | - Madalina Ghidersa
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, 700505 Iasi, Romania; (C.I.); (M.G.); (A.C.); (D.L.G.)
| | - Alin Ciobica
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, 700505 Iasi, Romania; (C.I.); (M.G.); (A.C.); (D.L.G.)
- “Ioan Haulica” Institute, Apollonia University, 700511 Iasi, Romania
- Center of Biomedical Research, Romanian Academy, Iasi Branch, 2 Teodor Codrescu Street, 700481 Iasi, Romania
| | - Ioannis Mavroudis
- Academy of Romanian Scientists, 050094 Bucharest, Romania
- Department of Neurosciences, Leeds Teaching Hospitals, Leeds LS9 7TF, UK
| | - Dimitrios Kazis
- Third Department of Neurology, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (D.K.); (F.E.P.)
| | - Foivos E. Petridis
- Third Department of Neurology, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece; (D.K.); (F.E.P.)
| | - Dragoș Lucian Gorgan
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, 700505 Iasi, Romania; (C.I.); (M.G.); (A.C.); (D.L.G.)
| | - Ioana-Miruna Balmus
- Department of Exact Sciences and Natural Sciences, Institute of Interdisciplinary Research, “Alexandru Ioan Cuza” University of Iasi, 700057 Iasi, Romania;
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Shah SS, Shetty AJ, Johnston DT, Hanan CL, O’Reilly BT, Skibber MA, Massoud AT, Zhu B, Sevick-Muraca EM, Juranek J, Cox CS, Shah MN. Implications and pathophysiology of neuroinflammation in pediatric patients with traumatic brain injury: an updated review. Front Neurosci 2025; 19:1587222. [PMID: 40303612 PMCID: PMC12037507 DOI: 10.3389/fnins.2025.1587222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Traumatic Brain Injury (TBI) in children is a profound public health issue with the potential to disrupt cognitive, behavioral, and psychosocial development significantly. This review provides an updated examination of the role of neuroinflammation in pediatric TBI, emphasizing its dual impact on injury progression and recovery. Highlighted is the complex interplay of primary and secondary injury mechanisms, including the critical contributions of neuroinflammatory responses mediated by central and peripheral immune cells. Advances in biomarker identification and imaging techniques are discussed, showcasing how tools like diffusion tensor imaging (DTI) and positron emission tomography (PET) enhance our understanding of neuroinflammatory processes. The review also explores current therapeutic strategies targeting neuroinflammation, underscoring emerging treatments such as pharmacologic agents that modulate immune responses and novel therapies like stem cell interventions. This comprehensive review seeks to deepen the understanding of neuroinflammation's pathophysiological roles in pediatric TBI and propose directions for future clinical and research efforts.
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Affiliation(s)
- Shalin S. Shah
- Department of Neurosurgery, UTHealth Houston, McGovern Medical School, Houston, TX, United States
| | - Arya J. Shetty
- Department of Neurosurgery, UTHealth Houston, McGovern Medical School, Houston, TX, United States
| | - David T. Johnston
- Department of Neurosurgery, UTHealth Houston, McGovern Medical School, Houston, TX, United States
| | - Caroline L. Hanan
- Department of Neurosurgery, UTHealth Houston, McGovern Medical School, Houston, TX, United States
| | - Brendan T. O’Reilly
- Department of Neurosurgery, UTHealth Houston, McGovern Medical School, Houston, TX, United States
| | - Max A. Skibber
- Department of Neurosurgery, UTHealth Houston, McGovern Medical School, Houston, TX, United States
| | - Ahmed T. Massoud
- Department of Neurosurgery, UTHealth Houston, McGovern Medical School, Houston, TX, United States
- Department of Pediatric Surgery, McGovern Medical School at UTHealth, Houston, TX, United States
| | - Banghe Zhu
- Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, UTHealth, Houston, TX, United States
| | - Eva M. Sevick-Muraca
- Center for Molecular Imaging, The Brown Foundation Institute of Molecular Medicine, UTHealth, Houston, TX, United States
| | - Jenifer Juranek
- Department of Pediatric Surgery, McGovern Medical School at UTHealth, Houston, TX, United States
| | - Charles S. Cox
- Department of Pediatric Surgery, McGovern Medical School at UTHealth, Houston, TX, United States
| | - Manish N. Shah
- Department of Neurosurgery, UTHealth Houston, McGovern Medical School, Houston, TX, United States
- Department of Pediatric Surgery, McGovern Medical School at UTHealth, Houston, TX, United States
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Makovec M, Skitek M, Šimnovec L, Jerin A. Neuron-Specific Enolase and S100B as Biomarkers of Ischemic Brain Injury During Surgery. Clin Pract 2025; 15:74. [PMID: 40310303 PMCID: PMC12026299 DOI: 10.3390/clinpract15040074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 03/26/2025] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Biochemical markers can be used in addition to neuroimaging techniques to evaluate the extent of ischemic brain injuries and to enable earlier diagnosis and faster intervention following the ischemic event. Among the potential biomarkers of ischemic brain injuries during surgery, neuron-specific enolase (NSE) and S100B are the most frequently studied and were shown to be the most promising. The aim of this review was to summarize the role of NSE and S100B as biomarkers of ischemic brain injuries that occur during selected surgical procedures, predominantly carotid endarterectomy (CEA). Some other invasive interventions that cause ischemic brain injuries, like extracorporeal membrane oxygenation, were also included. We can conclude that these biomarkers can be useful for the evaluation of ischemic brain injuries that occur during various surgical procedures. They can help to determine the most optimal conditions for performing the surgery and therefore improve the procedures to consequently minimize brain damage caused during surgery. Because of a significant delay between sample collection and obtaining the results, they are not suitable for real-time assessment of brain injuries. Some improvement can be expected with the future development of laboratory methods. The association of the changes in NSE and S100B levels during surgery with potential consequences of ischemic brain injury have been described in numerous studies. However, even in a very homogenous group of surgical procedures like CEA, these findings cannot be summarized into a common final conclusion; therefore, the prognostic value of the two markers is not clearly supported at the present time.
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Affiliation(s)
- Matej Makovec
- Department of Vascular Surgery, University Medical Centre Maribor, 2000 Maribor, Slovenia
| | - Milan Skitek
- Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, 1525 Ljubljana, Slovenia
| | - Leja Šimnovec
- Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, 1525 Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Aleš Jerin
- Institute of Clinical Chemistry and Biochemistry, University Medical Centre Ljubljana, 1525 Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
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Wang Y, Zhou Z, Zhang D, Jiang Y. Predictors of delayed encephalopathy after acute carbon monoxide poisoning: a literature review. Front Med (Lausanne) 2025; 12:1559264. [PMID: 40206479 PMCID: PMC11979149 DOI: 10.3389/fmed.2025.1559264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Accepted: 03/11/2025] [Indexed: 04/11/2025] Open
Abstract
Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is one of the severe complications that can occur after acute carbon monoxide poisoning (ACOP). The pathogenesis of DEACMP is complex, featuring a delitescence onset and poor prognosis. As a result, many scholars are concentrating on identifying predictors of DEACMP and evaluating their effects, including clinical characteristics, laboratory indicators, neuroelectrophysiology, imaging examination, and genetic susceptibility. However, current identified predictors lack consensus and their clinical application is limited. Therefore, we need to explore new predictors. Exosomes, the smallest extracellular vesicles (EVs) with nano-size, participate in both the physiological and pathological processes of the brain, and the changes in their content can provide valuable information for clinical diagnosis and evaluation of neurodegenerative diseases, suggesting that they may serve as a potential biomarker. However, the practicability of exosomes as biomarkers of DEACMP remains unclear. In the present review, we first introduced the pathogenesis of DEACMP and the currently identified predictors. Then, we also discussed the possibility of exosomes as the biomarkers of DEACMP, aiming to stimulate more attention and discussion on this topic, thereby providing meaningful insights for future research.
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Affiliation(s)
| | | | - Dailiang Zhang
- Clinical Medical College, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Yuan Jiang
- Clinical Medical College, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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Akel S, Axelsson M, Asztely F, Zetterberg H, Zelano J. Higher plasma neurofilament-light chain concentration in drug-resistant epilepsy. Brain Commun 2025; 7:fcaf108. [PMID: 40114782 PMCID: PMC11925020 DOI: 10.1093/braincomms/fcaf108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/30/2024] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
Drug-resistant epilepsy is the most severe form of epilepsy and is frequently associated with cognitive decline. Whether drug-resistant epilepsy results in neurodegeneration or other types of brain injury is not known, and early detection of detrimental clinical trajectories would be clinically very useful. Blood biomarkers of brain injury reflect neurodegeneration or brain injury in several brain diseases but have not been extensively studied in epilepsy. We investigated a panel of such markers in a large epilepsy cohort with an emphasis on assessing differences between drug-resistant and monotherapy-controlled epilepsy. Blood neurofilament light, glial fibrillary acidic protein, total tau, S100 calcium-binding protein B and neuron-specific enolase concentrations were measured in 444 patients (aged ≥ 18 years) with epilepsy participating in a prospective regional Biobank study in Västra Götaland (Sweden). Multiple linear regression assessed associations between clinical variables and marker levels. Levels were then compared between patients with drug-resistant epilepsy (n = 101) and patients with monotherapy-controlled epilepsy (n = 164). We also performed logistic regression analysis to evaluate the significance of the markers as predictors of epilepsy status (drug-resistant epilepsy or monotherapy-controlled epilepsy) while controlling for clinical variables: age, sex, epilepsy duration, epilepsy type and lesions. All markers correlated with age. In younger patients (≤50 years), cases of drug-resistant epilepsy had higher levels of neurofilament light (P = 0.002) and glial fibrillary acidic protein (P = 0.006) compared with monotherapy-controlled epilepsy. After excluding patients with known structural lesions, neurofilament light levels remained significantly elevated in drug-resistant epilepsy versus monotherapy-controlled epilepsy (P = 0.029). Neurofilament light also emerged as a significant predictor of drug-resistant status in a logistic regression model following adjustments for clinical variables. Future studies should explore if neurofilament light can be used for surveillance of disease course and whether it reflects brain injury in drug-resistant epilepsy.
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Affiliation(s)
- Sarah Akel
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, Gothenburg 41126, Sweden
| | - Markus Axelsson
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden
- Department of Neurology, Sahlgrenska University Hospital, Member of ERN Epicare, Gothenburg 41345, Sweden
| | - Fredrik Asztely
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden
- Department of Neurology, Angered Hospital, Angered 42422, Sweden
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal 43180, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 43180, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1E 6BT, UK
- UK Dementia Research Institute at UCL, London WC1E 6BT, UK
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong 1512-1518, China
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA
| | - Johan Zelano
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, Gothenburg 41126, Sweden
- Department of Neurology, Sahlgrenska University Hospital, Member of ERN Epicare, Gothenburg 41345, Sweden
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7
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Rix AC, Störmann P, Vollrath JT, Hörauf JA, Eichler K, Marzi I, Schindler CR. THE NEURONAL BIOMARKER NEURON-SPECIFIC ENOLASE CORRELATES WITH THE VOLUME OF LUNG CONTUSION IN POLYTRAUMATIZED PATIENTS. Shock 2025; 63:428-434. [PMID: 39227358 DOI: 10.1097/shk.0000000000002475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
ABSTRACT Background: Severe injuries caused by accidents, such as traumatic brain injury (TBI) or thoracic trauma (TT), continue to be the leading cause of death in younger people with relevant socioeconomic impact. Fast and targeted diagnostics is essential for further therapy decisions and prognosis. The following study investigates neuron-specific enolase (NSE) as a potential biomarker for lung injury after blunt TT. Methods: This is a retrospective analysis of prospectively collected data in a level 1 trauma center from 2014 to 2020. Serum levels of NSE and ILs (IL-6, IL-10) in injured patients (n = 41) with isolated TT (Abbreviated Injury Scale score of the thorax ≥3) compared with isolated TBI (Abbreviated Injury Scale score of the head ≥3) were assessed from days 0 to 5 after trauma. The extent of lung injury was quantified by Hounsfield scale in computed tomography scans. Results : Thirty patients with TT (median Injury Severity Score = 20, age 50 ± 17 years, 83.3% were male) and 11 patients with TBI (median Injury Severity Score = 25, age 54 ± 17 years, 27.3% were male) were included. After TT, NSE concentration increased initially after trauma with a peak value on the day of admission (8.51 ± 3.68 ng/mL) compared with healthy controls (4.51 ± 1.504 ng/mL, P < 0.001). Isolated TT and TBI lead to equally strong NSE release ad the day of admission. There is a significant linear relationship ( r = 0.636, P = 0.035) between serum NSE levels and severity of pulmonary contusion at the time of admission and after 24 h. Conclusion : A significant NSE release after isolated TT peaks on the day of admission. The extent of lung contusion volume (defined as alveolar parenchymal density) correlates with NSE serum concentration. Thus, NSE has predictive value for the extent of pulmonary contusion. However, according to these data, NSE seems to have no diagnostic value as a TBI biomarker in concomitant TT.
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Affiliation(s)
- Anna Carola Rix
- Department of Trauma-, Hand- and Reconstructive Surgery, University Hospital Frankfurt, Frankfurt, Germany
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8
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Lin Y, Li H, Song E, Lu Z, Dai Y, Zhang B. Serum neuron-specific enolase can predict the severity and outcome of anti-N-methyl-D-aspartate receptor encephalitis. Clin Chim Acta 2025; 565:119962. [PMID: 39244142 DOI: 10.1016/j.cca.2024.119962] [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: 09/16/2023] [Revised: 09/04/2024] [Accepted: 09/04/2024] [Indexed: 09/09/2024]
Abstract
BACKGROUND Little is known about the association between serum neuron-specific enolase (NSE) concentration and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study aims to investigate if serum NSE concentration is related to the clinical features of anti-NMDAR encephalitis. METHODS Serum NSE levels were detected in 58 anti-NMDAR encephalitis cases, 58 matched healthy controls and 58 matched disease controls. Demographic features, clinical symptoms, cerebrospinal fluid parameters and brain MRI indexes of the cases were evaluated. RESULTS Serum NSE concentrations were significant higher in case group than those in healthy controls and disease controls (both p < 0.001). Serum NSE concentrations in patients with mRS≥3 one year after onset were obviously higher than in those with mRS<3 (p < 0.001). Patients with status epilepticus or central hypoventilation had higher serum NSE levels than those without (p = 0.003 and p = 0.006). Serum NSE concentrations in cases with brain lesions or brain atrophy were significant higher than in those without (p = 0.001 and p < 0.001, respectively). Serum NSE concentrations were found to be significant higher in cases with limited response to treatment compared to those with favourable therapy outcomes (p < 0.001). Spearman's correlation analysis showed a significant positive association between serum NSE concentration and mRS score at the most critical time (max mRS) (r = 0.575, p < 0.001) and one year after onset (r = 0.705, p < 0.001). Cox regression results reflected that high serum NSE level was an independent predictor of poor prognosis in anti-NMDAR encephalitis group (p = 0.001), and the ROC curve threshold value was 15.72 ng/ml. CONCLUSIONS Serum NSE concentrations in anti-NMDAR encephalitis cases are higher than those in controls. It can be used to predict the brain damage degree and prognosis of anti-NMDAR encephalitis cases.
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Affiliation(s)
- Yinyao Lin
- Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, China
| | - Haiyan Li
- Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, China
| | - Enpeng Song
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, No. 2693 Kaichuang Avenue, Huangpu District, Guangzhou, Guangdong 510530, China
| | - Zhengqi Lu
- Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, China.
| | - Yongqiang Dai
- Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, China.
| | - Bingjun Zhang
- Department of Neurology, Mental and Neurological Disease Research Center, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, China.
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9
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Liang S, Hu Z. Unveiling the predictive power of biomarkers in traumatic brain injury: A narrative review focused on clinical outcomes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2024. [PMID: 39687991 DOI: 10.5507/bp.2024.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024] Open
Abstract
Traumatic brain injury (TBI) has long-term consequences, including neurodegenerative disease risk. Current diagnostic tools are limited in detecting subtle brain damage. This review explores emerging biomarkers for TBI, including those related to neuronal injury, inflammation, EVs, and ncRNAs, evaluating their potential to predict clinical outcomes like mortality, recovery, and cognitive impairment. It addresses challenges and opportunities for implementing biomarkers in clinical practice, aiming to improve TBI diagnosis, prognosis, and treatment.
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Affiliation(s)
- Sitao Liang
- Neurosurgery Department, Zhongshan City People's Hospital, Zhongshan, 528400, China
| | - Zihui Hu
- Neurosurgery Department, Zhongshan City People's Hospital, Zhongshan, 528400, China
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10
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Price AD, Baucom MR, Becker ER, Archdeacon CM, Smith MP, Caskey C, Schuster R, Blakeman TC, Strilka RJ, Pritts TA, Goodman MD. Systemic Inflammatory Effect of Hypobaria During Aeromedical Evacuation after Porcine Traumatic Brain Injury. J Am Coll Surg 2024; 239:430-442. [PMID: 38770953 DOI: 10.1097/xcs.0000000000001119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
BACKGROUND Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is used by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation after TBI that could contribute to more severe TBI-related secondary injury. STUDY DESIGN Thirty-six female pigs were used to test TBI vs Sham TBI, hypoxia vs normoxia, and hypobaria vs ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 ft were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO 2 while at altitude. Serum cytokines, ubiquitin C-terminal hydrolase L1, and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein and phosphorylated tau. RESULTS Serum interleukin-1β, interleukin-6, and tumor necrosis factor-α were significantly elevated after TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared with ground level/normoxia. No difference in TBI biomarkers after TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue glial fibrillary acidic protein or phosphorylated tau when comparing the most different conditions of Sham TBI + ground or normoxia with the TBI + hypobaria/hypoxia group was noted. CONCLUSIONS The hypobaric environment of AE induces systemic inflammation after TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE after TBI.
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Affiliation(s)
- Adam D Price
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Matthew R Baucom
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Ellen R Becker
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Chad M Archdeacon
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Maia P Smith
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Chelsea Caskey
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Rebecca Schuster
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Thomas C Blakeman
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Richard J Strilka
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
- United States Air Force Center for Sustainment of Trauma and Readiness Skills, Cincinnati, OH (Strilka)
| | - Timothy A Pritts
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
| | - Michael D Goodman
- From the Department of Surgery, University of Cincinnati, Cincinnati, OH (Price, Baucom, Becker, Archdeacon, Smith, Caskey, Schuster, Blakeman, Strilka, Pritts, Goodman)
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Yadav P, Nasir F, Sivanandam TM. Neuroprotective effect of vitamin B 12 supplementation on cognitive functions and neuronal morphology at different time intervals after traumatic brain injury in male Swiss albino mice. Neurochem Int 2024; 180:105869. [PMID: 39332530 DOI: 10.1016/j.neuint.2024.105869] [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: 07/15/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 09/29/2024]
Abstract
Traumatic brain injury is a highly irreversible process that consists of primary as well as secondary injury which develops and progresses over months to years, leading to cognitive dysfunctions. Vitamin B12 received considerable interest due to its potential therapeutic properties. The pathways of vitamin B12 are closely related to neuronal survival but its effects on the pathophysiology of injury with respect to cognition is a relatively unexplored area of research. In this study, we investigated, the effect of vitamin B12 and its involvement in neuroprotection on TBI-induced pathophysiology in male Swiss albino mice. Our findings suggested that vitamin B12 supplementation improves TBI-mediated neurological impairments, spatial and recognition memory, and anxiety-like behavior. Furthermore, the oxidative stress was reduced by declined homocysteine level with vitamin B12 supplementation validating declined expression of astrocytes and TBI biomarkers. The studies on neuronal morphology revealed that vitamin B12 supplementation increases the dendritic arborization and density of mushroom and filopodia-shaped spines and further increases the expression of synaptic plasticity-related genes and proteins. Taken together, our findings reveal that, supplementation of vitamin B12 restored the TBI-induced downregulation of dendritic arborization, and spine density which ultimately increases synaptic plasticity, cell survival, and recovery of cognitive dysfunctions.
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Affiliation(s)
- Priyanka Yadav
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
| | - Farheen Nasir
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
| | - Thamil Mani Sivanandam
- Biochemistry and Molecular Biology Laboratory, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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12
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El-Menyar A, Asim M, Khan N, Rizoli S, Mahmood I, Al-Ani M, Kanbar A, Alaieb A, Hakim S, Younis B, Taha I, Jogol H, Siddiqui T, Hammo AA, Abdurraheim N, Alabdallat M, Bahey AAA, Ahmed K, Atique S, Chaudry IH, Prabhu KS, Uddin S, Al-Thani H. Systemic and cerebro-cardiac biomarkers following traumatic brain injury: an interim analysis of randomized controlled clinical trial of early administration of beta blockers. Sci Rep 2024; 14:19574. [PMID: 39179700 PMCID: PMC11343837 DOI: 10.1038/s41598-024-70470-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 08/16/2024] [Indexed: 08/26/2024] Open
Abstract
This is an interim analysis of the Beta-blocker (Propranolol) use in traumatic brain injury (TBI) based on the high-sensitive troponin status (BBTBBT) study. The BBTBBT is an ongoing double-blind placebo-controlled randomized clinical trial with a target sample size of 771 patients with TBI. We sought, after attaining 50% of the sample size, to explore the impact of early administration of beta-blockers (BBs) on the adrenergic surge, pro-inflammatory cytokines, and the TBI biomarkers linked to the status of high-sensitivity troponin T (HsTnT). Patients were stratified based on the severity of TBI using the Glasgow coma scale (GCS) and HsTnT status (positive vs negative) before randomization. Patients with positive HsTnT (non-randomized) received propranolol (Group-1; n = 110), and those with negative test were randomized to receive propranolol (Group-2; n = 129) or placebo (Group-3; n = 111). Propranolol was administered within 24 h of injury for 6 days, guided by the heart rate (> 60 bpm), systolic blood pressure (≥ 100 mmHg), or mean arterial pressure (> 70 mmHg). Luminex and ELISA-based immunoassays were used to quantify the serum levels of pro-inflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, and IL-18), TBI biomarkers [S100B, Neuron-Specific Enolase (NSE), and epinephrine]. Three hundred and fifty patients with comparable age (mean 34.8 ± 9.9 years) and gender were enrolled in the interim analysis. Group 1 had significantly higher baseline levels of IL-6, IL-1B, S100B, lactate, and base deficit than the randomized groups (p = 0.001). Group 1 showed a significant temporal reduction in serum IL-6, IL-1β, epinephrine, and NSE levels from baseline to 48 h post-injury (p = 0.001). Patients with severe head injuries had higher baseline levels of IL-6, IL-1B, S100B, and HsTnT than mild and moderate TBI (p = 0.01). HsTnT levels significantly correlated with the Injury Severity Score (ISS) (r = 0.275, p = 0.001), GCS (r = - 0.125, p = 0.02), and serum S100B (r = 0.205, p = 0.001). Early Propranolol administration showed a significant reduction in cytokine levels and TBI biomarkers from baseline to 48 h post-injury, particularly among patients with positive HsTnT, indicating the potential role in modulating inflammation post-TBI.Trial registration: ClinicalTrials.gov NCT04508244. It was registered first on 11/08/2020. Recruitment started on 29 December 2020 and is ongoing. The study was partly presented at the 23rd European Congress of Trauma and Emergency Surgery (ECTES), April 28-30, 2024, in Estoril, Lisbon, Portugal.
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Affiliation(s)
- Ayman El-Menyar
- Department of Surgery, Clinical Research, Trauma and Vascular Surgery, Hamad Medical Corporation, Doha, Qatar.
- Department of Clinical Medicine, Weill Cornell Medicine, P.O. Box 24144, Doha, Qatar.
| | - Mohammad Asim
- Department of Surgery, Clinical Research, Trauma and Vascular Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Naushad Khan
- Department of Surgery, Clinical Research, Trauma and Vascular Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Sandro Rizoli
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Ismail Mahmood
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Mushreq Al-Ani
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Ahad Kanbar
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Abubaker Alaieb
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Suhail Hakim
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Basil Younis
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Ibrahim Taha
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Hisham Jogol
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Tariq Siddiqui
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Abdel Aziz Hammo
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Nuri Abdurraheim
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Mohammad Alabdallat
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | | | - Khalid Ahmed
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Sajid Atique
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
| | - Irshad H Chaudry
- Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Hassan Al-Thani
- Department of Surgery, Trauma Surgery, Hamad Medical Corporation, Doha, Qatar
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13
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Wongsripuemtet P, Ohnuma T, Temkin N, Barber J, Komisarow J, Manley GT, Hatfield J, Treggiari M, Colton K, Sasannejad C, Chaikittisilpa N, Ivins-O'Keefe K, Grandhi R, Laskowitz D, Mathew JP, Hernandez A, James ML, Raghunathan K, Miller J, Vavilala M, Krishnamoorthy V. Association of early dexmedetomidine exposure with brain injury biomarker levels following moderate - Severe traumatic brain injury: A TRACK-TBI study. J Clin Neurosci 2024; 126:338-347. [PMID: 39029302 DOI: 10.1016/j.jocn.2024.07.003] [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: 03/27/2024] [Revised: 07/02/2024] [Accepted: 07/03/2024] [Indexed: 07/21/2024]
Abstract
BACKGROUND Traumatic brain injury (TBI) triggers autonomic dysfunction and inflammatory response that can result in secondary brain injuries. Dexmedetomidine is an alpha-2 agonist that may modulate autonomic function and inflammation and has been increasingly used as a sedative agent for critically ill TBI patients. We aimed to investigate the association between early dexmedetomidine exposure and blood-based biomarker levels in moderate-to-severe TBI (msTBI). METHODS We conducted a retrospective cohort study using data from the Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study (TRACK-TBI), which enrolled acute TBI patients prospectively across 18 United States Level 1 trauma centers between 2014-2018. Our study population focused on adults with msTBI defined by Glasgow Coma Scale score 3-12 after resuscitation, who required mechanical ventilation and sedation within the first 48 h of ICU admission. The study's exposure was early dexmedetomidine utilization (within the first 48 h of admission). Primary outcome included brain injury biomarker levels measured from circulating blood on day 3 following injury, including glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B) and the inflammatory biomarker C-reactive protein (CRP). Secondary outcomes assessed biomarker levels on days 5 and 14. Linear mixed-effects regression modelling of the log-transformed response variable was used to analyze the association of early dexmedetomidine exposure with brain injury biomarker levels. RESULTS Among the 352 TRACK-TBI subjects that met inclusion criteria, 50 (14.2 %) were exposed to early dexmedetomidine, predominantly male (78 %), white (81 %), and non-Hispanic (81 %), with mean age of 39.8 years. Motor vehicle collisions (27 %) and falls (22 %) were common causes of injury. No significant associations were found between early dexmedetomidine exposure with day 3 brain injury biomarker levels (GFAP, ratio = 1.46, 95 % confidence interval [0.90, 2.34], P = 0.12; UCH-L1; ratio = 1.17 [0.89, 1.53], P = 0.26; NSE, ratio = 1.19 [0.92, 1.53], P = 0.19; S100B, ratio = 1.01 [0.95, 1.06], P = 0.82; hs-CRP, ratio = 1.29 [0.91, 1.83], P = 0.15). The hs-CRP level at day 14 in the dexmedetomidine group was higher than that of the non-exposure group (ratio = 1.62 [1.12, 2.35], P = 0.012). CONCLUSIONS There were no significant associations between early dexmedetomidine exposure and day 3 brain injury biomarkers in msTBI. Our findings suggest that early dexmedetomidine use is not correlated with either decrease or increase in brain injury biomarkers following msTBI. Further research is necessary to confirm these findings.
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Affiliation(s)
- Pattrapun Wongsripuemtet
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | - Tetsu Ohnuma
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Anesthesiology, Duke University, Durham, NC, United States
| | - Nancy Temkin
- Department of Biostatistics, University of Washington, Seattle, WA, United States; Department of Neurosurgery, University of Washington, Seattle, WA, United States
| | - Jason Barber
- Department of Biostatistics, University of Washington, Seattle, WA, United States
| | - Jordan Komisarow
- Department of Neurosurgery, Duke University, Durham, NC, United States
| | - Geoffrey T Manley
- Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, CA, United States
| | - Jordan Hatfield
- Department of Neurosurgery, Duke University, Durham, NC, United States; Duke University School of Medicine, Durham, NC, United States
| | - Miriam Treggiari
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Anesthesiology, Duke University, Durham, NC, United States
| | - Katharine Colton
- Department of Neurology, Duke University, Durham, NC, United States
| | - Cina Sasannejad
- Department of Neurology, Duke University, Durham, NC, United States
| | - Nophanan Chaikittisilpa
- Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kelly Ivins-O'Keefe
- Department of Anesthesiology, Duke University, Durham, NC, United States; Duke University School of Medicine, Durham, NC, United States
| | - Ramesh Grandhi
- Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
| | - Daniel Laskowitz
- Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Neurosurgery, Duke University, Durham, NC, United States; Department of Neurology, Duke University, Durham, NC, United States
| | - Joseph P Mathew
- Department of Anesthesiology, Duke University, Durham, NC, United States
| | - Adrian Hernandez
- Department of Medicine, Duke University, Durham, NC, United States
| | - Michael L James
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Neurology, Duke University, Durham, NC, United States
| | - Karthik Raghunathan
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Population Health Sciences, Duke University, Durham, NC, United States
| | - Joseph Miller
- Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
| | - Monica Vavilala
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States
| | - Vijay Krishnamoorthy
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Anesthesiology, Duke University, Durham, NC, United States; Department of Population Health Sciences, Duke University, Durham, NC, United States
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14
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Karimova D, Rostami E, Chubarev VN, Tarasov VV, Schiöth HB, Rask-Andersen M. Advances in development of biomarkers for brain damage and ischemia. Mol Biol Rep 2024; 51:803. [PMID: 39001884 PMCID: PMC11246271 DOI: 10.1007/s11033-024-09708-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 06/06/2024] [Indexed: 07/15/2024]
Abstract
Acquired brain injury is an urgent situation that requires rapid diagnosis and treatment. Magnetic resonance imaging (MRI) and computed tomography (CT) are required for accurate diagnosis. However, these methods are costly and require substantial infrastructure and specialized staff. Circulatory biomarkers of acute brain injury may help in the management of patients with acute cerebrovascular events and prevent poor outcome and mortality. The purpose of this review is to provide an overview of the development of potential biomarkers of brain damage to increase diagnostic possibilities. For this purpose, we searched the PubMed database of studies on the diagnostic potential of brain injury biomarkers. We also accessed information from Clinicaltrials.gov to identify any clinical trials of biomarker measurements for the diagnosis of brain damage. In total, we present 41 proteins, enzymes and hormones that have been considered as biomarkers for brain injury, of which 20 have been studied in clinical trials. Several microRNAs have also emerged as potential clinical biomarkers for early diagnosis. Combining multiple biomarkers in a panel, along with other parameters, is yielding promising outcomes.
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Affiliation(s)
- Diana Karimova
- Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala, University, Uppsala, Sweden
| | - Elham Rostami
- Department of Medical Sciences, Section of Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Vladimir N Chubarev
- Advanced Molecular Technology, Limited Liable Company (LLC), Moscow, 354340, Russia
| | - Vadim V Tarasov
- Advanced Molecular Technology, Limited Liable Company (LLC), Moscow, 354340, Russia
| | - Helgi B Schiöth
- Functional Pharmacology and Neuroscience, Department of Surgical Sciences, Uppsala, University, Uppsala, Sweden
| | - Mathias Rask-Andersen
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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15
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Horvat S, Kos J, Pišlar A. Multifunctional roles of γ-enolase in the central nervous system: more than a neuronal marker. Cell Biosci 2024; 14:61. [PMID: 38735971 PMCID: PMC11089681 DOI: 10.1186/s13578-024-01240-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 04/27/2024] [Indexed: 05/14/2024] Open
Abstract
Enolase, a multifunctional protein with diverse isoforms, has generally been recognized for its primary roles in glycolysis and gluconeogenesis. The shift in isoform expression from α-enolase to neuron-specific γ-enolase extends beyond its enzymatic role. Enolase is essential for neuronal survival, differentiation, and the maturation of neurons and glial cells in the central nervous system. Neuron-specific γ-enolase is a critical biomarker for neurodegenerative pathologies and neurological conditions, not only indicating disease but also participating in nerve cell formation and neuroprotection and exhibiting neurotrophic-like properties. These properties are precisely regulated by cysteine peptidase cathepsin X and scaffold protein γ1-syntrophin. Our findings suggest that γ-enolase, specifically its C-terminal part, may offer neuroprotective benefits against neurotoxicity seen in Alzheimer's and Parkinson's disease. Furthermore, although the therapeutic potential of γ-enolase seems promising, the effectiveness of enolase inhibitors is under debate. This paper reviews the research on the roles of γ-enolase in the central nervous system, especially in pathophysiological events and the regulation of neurodegenerative diseases.
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Affiliation(s)
- Selena Horvat
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
| | - Janko Kos
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia
- Department of Biotechnology, Jožef Stefan Institute, Jamova Cesta 39, 1000, Ljubljana, Slovenia
| | - Anja Pišlar
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
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16
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Andreou D, Steen NE, Mørch-Johnsen L, Jørgensen KN, Wortinger LA, Barth C, Szabo A, O'Connell KS, Lekva T, Hjell G, Johansen IT, Ormerod MBEG, Haukvik UK, Aukrust P, Djurovic S, Yolken RH, Andreassen OA, Ueland T, Agartz I. Toxoplasma gondii infection associated with inflammasome activation and neuronal injury. Sci Rep 2024; 14:5327. [PMID: 38438515 PMCID: PMC10912117 DOI: 10.1038/s41598-024-55887-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 02/28/2024] [Indexed: 03/06/2024] Open
Abstract
Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.
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Affiliation(s)
- Dimitrios Andreou
- Department of Psychiatric Research, Diakonhjemmet Hospital, Forskningsveien 7, 0373, Oslo, Norway.
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
| | - Nils Eiel Steen
- Department of Psychiatric Research, Diakonhjemmet Hospital, Forskningsveien 7, 0373, Oslo, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Lynn Mørch-Johnsen
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychiatry and Department of Clinical Research, Østfold Hospital, Grålum, Norway
| | - Kjetil Nordbø Jørgensen
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Mental Health and Addiction, Vestre Viken Hospital Trust, Drammen, Norway
| | - Laura A Wortinger
- Department of Psychiatric Research, Diakonhjemmet Hospital, Forskningsveien 7, 0373, Oslo, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Claudia Barth
- Department of Psychiatric Research, Diakonhjemmet Hospital, Forskningsveien 7, 0373, Oslo, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Attila Szabo
- Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Kevin S O'Connell
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Tove Lekva
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Gabriela Hjell
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychiatry and Department of Clinical Research, Østfold Hospital, Grålum, Norway
| | - Ingrid Torp Johansen
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Monica B E G Ormerod
- Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Unn K Haukvik
- Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Department of Forensic Research and Education, Oslo University Hospital, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Srdjan Djurovic
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Robert H Yolken
- Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ole A Andreassen
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Ingrid Agartz
- Department of Psychiatric Research, Diakonhjemmet Hospital, Forskningsveien 7, 0373, Oslo, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
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17
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Pei M, Yang Y, Zhang C, Huang Q, Fang Y, Xu L, Lin S, He H. Role of serum neuron-specific enolase levels in the early diagnosis and prognosis of sepsis-associated encephalopathy: a systematic review and meta-analysis. Front Neurol 2024; 15:1353063. [PMID: 38685952 PMCID: PMC11057363 DOI: 10.3389/fneur.2024.1353063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/12/2024] [Indexed: 05/02/2024] Open
Abstract
Background Sepsis-associated encephalopathy (SAE) is one of the most ubiquitous complications of sepsis and is characterized by cognitive impairment, poor prognosis, and a lack of uniform clinical diagnostic criteria. Therefore, this study investigated the early diagnostic and prognostic value of serum neuron-specific enolase (NSE) in SAE. Methods This systematic review and meta-analysis systematically searched for clinical trials with serum NSE information in patients with sepsis in the PubMed, Web of Science, Embase, and Cochrane databases from their inception to April 10, 2023. Included studies were assessed for quality and risk of bias using The Quality Assessment of Diagnostic Accuracy-2 tool. The meta-analysis of the included studies was performed using Stata 17.0 and Review Manager version 5.4. Findings Eleven studies were included in this meta-analysis involving 1259 serum samples from 947 patients with sepsis. Our results showed that the serum NSE levels of patients with SAE were higher than those of the non-encephalopathy sepsis group (mean deviation, MD,12.39[95% CI 8.27-16.50, Z = 5.9, p < 0.00001]), and the serum NSE levels of patients with sepsis who died were higher than those of survivors (MD,4.17[95% CI 2.66-5.68, Z = 5.41, p < 0.00001]). Conclusion Elevated serum NSE levels in patients with sepsis are associated with the early diagnosis of SAE and mortality; therefore, serum NSE probably is a valid biomarker for the early diagnosis and prognosis of patients with SAE. Systematic review registration This study was registered in PROSPERO, CRD42023433111.
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Affiliation(s)
- MengQin Pei
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - YuShen Yang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - ChunYan Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - QiaoMei Huang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - YuMing Fang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - LiMing Xu
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - HeFan He
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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Mochetti MM, Silva EGP, Correa AAF, Cabette MR, Perissinotti IN, E Silva LOJ, Pessoa ADS, de Oliveira RC, da Silva LFF, de Souza HP, de Alencar JCG. Neuron-specific enolase at admission as a predictor for stroke volume, severity and outcome in ischemic stroke patients: a prognostic biomarker review. Sci Rep 2024; 14:2688. [PMID: 38302568 PMCID: PMC10834412 DOI: 10.1038/s41598-024-53080-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 01/27/2024] [Indexed: 02/03/2024] Open
Abstract
An ideal blood biomarker for stroke should provide reliable results, enable fast diagnosis, and be readily accessible for practical use. Neuron-specific enolase (NSE), an enzyme released after neuronal damage, has been studied as a marker for brain injury, including cerebral infarction. However, different methodologies and limited sample sizes have restricted the applicability of any potential findings. This work aims to determine whether NSE levels at Emergency Department (ED) admission correlate with stroke severity, infarcted brain volume, functional outcome, and/or death rates. A systematic literature review was performed using PubMed, Embase, and Scopus databases. Each reviewer independently assessed all published studies identified as potentially relevant. All relevant original observational studies (cohort, case-control, and cross-sectional studies) were included. Eleven studies (1398 patients) met the inclusion criteria. Among these, six studies reported a significant correlation between NSE levels and stroke severity, while only one found no association. Four studies indicated a positive relationship between infarcted brain volume assessed by imaging and NSE levels, in contrast to the findings of only one study. Four studies identified an association related to functional outcome and death rates, while three others did not reach statistical significance in their findings. These data highlight that NSE levels at ED admissions proved to be a promising tool for predicting the outcome of ischemic stroke patients in most studies. However, they presented high discrepancies and low robustness. Therefore, further research is necessary to establish and define the role of NSE in clinical practice.
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Affiliation(s)
- Matheus Menão Mochetti
- Curso de Medicina, Faculdade de Odontologia de Bauru, Universidade de São Paulo, Bauru, Brazil.
| | | | | | | | - Iago Navas Perissinotti
- Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | | | - Adriano de Souza Pessoa
- Departamento de Ciências Biológicas, Faculdade de Odontologia de Bauru, Universidade de São Paulo, Bauru, Brazil
| | - Rodrigo Cardoso de Oliveira
- Departamento de Ciências Biológicas, Faculdade de Odontologia de Bauru, Universidade de São Paulo, Bauru, Brazil
| | | | - Heraldo Possolo de Souza
- Disciplina de Emergências Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Júlio César Garcia de Alencar
- Curso de Medicina, Faculdade de Odontologia de Bauru, Universidade de São Paulo, Bauru, Brazil
- Disciplina de Emergências Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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19
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Bhadani KH, Sankar J, Datta SK, Tungal S, Jat KR, Kabra SK, Lodha R. Validation of a Clinical Tool to Predict Neurological Outcomes in Critically Ill Children-A Prospective Observational Study. Indian J Pediatr 2024; 91:10-16. [PMID: 36949369 DOI: 10.1007/s12098-023-04482-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/09/2022] [Indexed: 03/24/2023]
Abstract
OBJECTIVES To evaluate the performance of the empiric tool by Gupta et al. in predicting neurological outcomes in children admitted to the pediatric intensive care unit (PICU) and to evaluate the association of biomarkers S100B and NSE with neurological outcomes. METHODS This prospective observational study was conducted in 163 critically ill children aged 2 mo to 17 y admitted to the PICU from June 2020 to July 2021. The authors used the prediction tool developed by Gupta et al.; the tool was applied at admission and at PICU discharge/death. Samples for NSE and S100B were collected at admission and discharge. The performance of the new tool was assessed through discrimination and calibration. Risk factors for "unfavorable outcomes" (decline in PCPC score by > 1) were evaluated by multivariate analysis. RESULTS The PICU mortality was 28% (n = 45). When the tool developed by Gupta et al. was used at the time of admission, favorable neurological outcomes were predicted for 69% (112) children. The area under the curve for the new tool at admission was 0.72 and at discharge/death it was 0.99, and the calibration was excellent at both time points. Independent factors associated with unfavorable neurological outcomes were higher PCPC scores and organ failure. As the number of samples processed for NSE and S100B was less, statistical analysis was not attempted. CONCLUSIONS The new tool by Gupta et al. has good discrimination, calibration, sensitivity, and specificity and can be used as a prediction tool. NSE and S100B are promising biomarkers and need further evaluation.
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Affiliation(s)
| | - Jhuma Sankar
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
| | - Sudip Kumar Datta
- Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Sagar Tungal
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Kana Ram Jat
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Sushil K Kabra
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Rakesh Lodha
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
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20
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Zhang Y, Li Z, Wang H, Pei Z, Zhao S. Molecular biomarkers of diffuse axonal injury: recent advances and future perspectives. Expert Rev Mol Diagn 2024; 24:39-47. [PMID: 38183228 DOI: 10.1080/14737159.2024.2303319] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 12/18/2023] [Indexed: 01/07/2024]
Abstract
INTRODUCTION Diffuse axonal injury (DAI), with high mortality and morbidity both in children and adults, is one of the most severe pathological consequences of traumatic brain injury. Currently, clinical diagnosis, disease assessment, disability identification, and postmortem diagnosis of DAI is mainly limited by the absent of specific molecular biomarkers. AREAS COVERED In this review, we first introduce the pathophysiology of DAI, summarized the reported biomarkers in previous animal and human studies, and then the molecular biomarkers such as β-Amyloid precursor protein, neurofilaments, S-100β, myelin basic protein, tau protein, neuron-specific enolase, Peripherin and Hemopexin for DAI diagnosis is summarized. Finally, we put forward valuable views on the future research direction of diagnostic biomarkers of DAI. EXPERT OPINION In recent years, the advanced technology has ultimately changed the research of DAI, and the numbers of potential molecular biomarkers was introduced in related studies. We summarized the latest updated information in such studies to provide references for future research and explore the potential pathophysiological mechanism on diffuse axonal injury.
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Affiliation(s)
- Youyou Zhang
- Department of Geriatrics Neurology, the Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Linfen People's Hosiptal, the Seventh Clinical Medical College of Shanxi Medical University, Linfen, Shanxi, China
| | - Zhaoyang Li
- Department of Occupational and Environmental Health, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hui Wang
- Department of Geriatrics Neurology, the Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhiyong Pei
- Linfen People's Hosiptal, the Seventh Clinical Medical College of Shanxi Medical University, Linfen, Shanxi, China
| | - Shuquan Zhao
- Department of Forensic Pathology, Zhongshan School of Medicine Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, China
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21
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Tsuchiya R, Ooigawa H, Kimura T, Tabata S, Maeda T, Sato H, Suzuki K, Ohara Y, Ooya Y, Nemoto M, Kurita H. Study of certain easily available biochemical markers in prognostication in severe traumatic brain injury requiring surgery. Surg Neurol Int 2023; 14:410. [PMID: 38213429 PMCID: PMC10783664 DOI: 10.25259/sni_544_2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/31/2023] [Indexed: 01/13/2024] Open
Abstract
Background This study aimed to identify easily available prognostic factors in severe traumatic brain injury (TBI) patients undergoing craniotomy. Methods We retrospectively analyzed the clinical characteristics (age, sex, Glasgow coma scale score, cause of TBI, and oral antithrombotic drug use), laboratory parameters (hemoglobin, sodium, C-reactive protein, D-dimer, activated partial thromboplastin time, prothrombin time-international normalized ratio, and glucose-potassium [GP] ratio), and neuroradiological findings of 132 patients who underwent craniotomy for severe TBI in our hospital between January 2015 and December 2021. The patients were divided into two groups: Those with fatal clinical outcomes and those with non-fatal clinical outcomes, and compared between the two groups. Results The patients comprised 79 (59.8%) male and 53 (40.2%) female patients. Their mean age was 67 ± 17 years (range, 16-94 years). Computed tomography revealed acute subdural hematoma in 108 (81.8%) patients, acute epidural hematoma in 31 (23.5%), traumatic brain contusion in 39 (29.5%), and traumatic subarachnoid hemorrhage in 62 (47.0%). All 132 patients underwent craniotomy, and 41 eventually died. There were significant differences in the D-dimer, GP ratio, and optic nerve sheath diameter between the groups (all P < 0.01). Multivariate logistic regression analysis showed elevated GP ratio and D-dimer were associated with the death group (P < 0.01, P < 0.01, respectively). A GP ratio of >42 was the optimal cutoff value for the prediction of a fatal outcome of TBI (sensitivity, 85.4%; specificity, 51.1%). Conclusion The GP ratio and D-dimer were significantly associated with poor outcomes of TBI. A GP ratio of >42 could be a predictor of a fatal outcome of TBI.
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Affiliation(s)
- Ryosuke Tsuchiya
- Department of Neurosurgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Hidetoshi Ooigawa
- Department of Neurosurgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Tatsuki Kimura
- Department of Neurosurgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Shinya Tabata
- Department of Neurosurgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Takuma Maeda
- Department of Neurosurgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Hiroki Sato
- Department of Neurosurgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Kaima Suzuki
- Department of Neurosurgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Yasuhiro Ohara
- Department of Critical Care and Emergency, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Yoshitaka Ooya
- Department of Critical Care and Emergency, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Manabu Nemoto
- Department of Critical Care and Emergency, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
| | - Hiroki Kurita
- Department of Neurosurgery, Saitama Medical University International Medical Center, Yamane, Hidaka, Japan
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22
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Agoston DV, Helmy A. Fluid-Based Protein Biomarkers in Traumatic Brain Injury: The View from the Bedside. Int J Mol Sci 2023; 24:16267. [PMID: 38003454 PMCID: PMC10671762 DOI: 10.3390/ijms242216267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/07/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
There has been an explosion of research into biofluid (blood, cerebrospinal fluid, CSF)-based protein biomarkers in traumatic brain injury (TBI) over the past decade. The availability of very large datasets, such as CENTRE-TBI and TRACK-TBI, allows for correlation of blood- and CSF-based molecular (protein), radiological (structural) and clinical (physiological) marker data to adverse clinical outcomes. The quality of a given biomarker has often been framed in relation to the predictive power on the outcome quantified from the area under the Receiver Operating Characteristic (ROC) curve. However, this does not in itself provide clinical utility but reflects a statistical association in any given population between one or more variables and clinical outcome. It is not currently established how to incorporate and integrate biofluid-based biomarker data into patient management because there is no standardized role for such data in clinical decision making. We review the current status of biomarker research and discuss how we can integrate existing markers into current clinical practice and what additional biomarkers do we need to improve diagnoses and to guide therapy and to assess treatment efficacy. Furthermore, we argue for employing machine learning (ML) capabilities to integrate the protein biomarker data with other established, routinely used clinical diagnostic tools, to provide the clinician with actionable information to guide medical intervention.
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Affiliation(s)
- Denes V. Agoston
- Department of Anatomy, Physiology and Genetic, School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA
| | - Adel Helmy
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK;
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23
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Nübel J, Buhre C, Hoffmeister M, Oess S, Labrenz O, Jost K, Hauptmann M, Schön J, Fritz G, Butter C, Haase-Fielitz A. Association between Neuron-Specific Enolase, Memory Function, and Postoperative Delirium after Transfemoral Aortic Valve Replacement. J Cardiovasc Dev Dis 2023; 10:441. [PMID: 37998499 PMCID: PMC10672434 DOI: 10.3390/jcdd10110441] [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: 09/21/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 11/25/2023] Open
Abstract
INTRODUCTION Although transfemoral aortic valve replacement (TAVR) is a safe treatment for elderly patients with severe aortic valve stenosis, postoperative microembolism has been described. In this secondary endpoint analysis of the POST-TAVR trial, we aimed to investigate whether changes in neuron-specific enolase (NSE)-a biomarker of neuronal damage-are associated with changes in memory function or postoperative delirium (POD). MATERIALS AND METHODS This was a prospective single-center study enrolling patients undergoing elective TAVR. Serum NSE was measured before and 24 h after TAVR. POD was diagnosed using CAM-ICU testing. Memory function was assessed before TAVR and before hospital discharge using the "Consortium to Establish a Registry for Alzheimer's Disease" (CERAD) word list and the digit span task (DST) implemented in "∆elta-App". RESULTS Subjects' median age was 82 years (25th to 75th percentile: 77.5-85.0), 42.6% of subjects were women. CERAD scores significantly increased from pre- to post-TAVR, with p < 0.001. POD occurred in 4.4% (6/135) of subjects at median 2 days after TAVR. After TAVR, NSE increased from a median of 1.85 ng/mL (1.30-2.53) to 2.37 ng/mL (1.69-3.07), p < 0.001. The median increase in NSE was 40.4% (13.1-138.0) in patients with POD versus 17.3% (3.3-43.4) in those without POD (p = 0.17). CONCLUSIONS Memory function improved after TAVR, likely due to learning effects, with no association to change in NSE. Patients with POD appear to have significantly higher postoperative levels of NSE compared to patients without POD after TAVR. This finding suggests that neuronal damage, as indicated by NSE elevation, may not significantly impair assessed memory function after TAVR.
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Affiliation(s)
- Jonathan Nübel
- Department of Cardiology, University Hospital Heart Centre Brandenburg, Brandenburg Medical School Theodor Fontane, 16321 Bernau, Germany
- Faculty of Health Sciences (FGW), Joint Faculty of the University of Potsdam, The Brandenburg Medical School Theodor Fontane and the Brandenburg Technical University Cottbus-Senftenberg, 16816 Cottbus, Germany
| | - Charlotte Buhre
- Department of Cardiology, University Hospital Heart Centre Brandenburg, Brandenburg Medical School Theodor Fontane, 16321 Bernau, Germany
- Faculty of Health Sciences (FGW), Joint Faculty of the University of Potsdam, The Brandenburg Medical School Theodor Fontane and the Brandenburg Technical University Cottbus-Senftenberg, 16816 Cottbus, Germany
| | - Meike Hoffmeister
- Faculty of Health Sciences (FGW), Joint Faculty of the University of Potsdam, The Brandenburg Medical School Theodor Fontane and the Brandenburg Technical University Cottbus-Senftenberg, 16816 Cottbus, Germany
- Institute of Biochemistry, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
| | - Stefanie Oess
- Faculty of Health Sciences (FGW), Joint Faculty of the University of Potsdam, The Brandenburg Medical School Theodor Fontane and the Brandenburg Technical University Cottbus-Senftenberg, 16816 Cottbus, Germany
- Institute of Biochemistry, Brandenburg Medical School Theodor Fontane, 14770 Brandenburg an der Havel, Germany
| | - Oliver Labrenz
- Department of Psychology, Brandenburg Medical School Theodor Fontane, 16816 Neuruppin, Germany
| | - Kerstin Jost
- Department of Psychology, Brandenburg Medical School Theodor Fontane, 16816 Neuruppin, Germany
| | - Michael Hauptmann
- Faculty of Health Sciences (FGW), Joint Faculty of the University of Potsdam, The Brandenburg Medical School Theodor Fontane and the Brandenburg Technical University Cottbus-Senftenberg, 16816 Cottbus, Germany
- Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, 16816 Neuruppin, Germany
| | - Julika Schön
- Anesthesia and Intensive Care, University Hospital Ruppin Brandenburg (UKRB), Brandenburg Medical School Theodor Fontane, 16816 Neuruppin, Germany
| | - Georg Fritz
- Department of Anesthesiology, Intensive Care and Pain Therapy, University Hospital Heart Centre Brandenburg, Brandenburg Medical School Theodor Fontane, 16321 Bernau, Germany
| | - Christian Butter
- Department of Cardiology, University Hospital Heart Centre Brandenburg, Brandenburg Medical School Theodor Fontane, 16321 Bernau, Germany
| | - Anja Haase-Fielitz
- Department of Cardiology, University Hospital Heart Centre Brandenburg, Brandenburg Medical School Theodor Fontane, 16321 Bernau, Germany
- Institute of Social Medicine and Health System Research, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany
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Chiperi LE, Huţanu A, Tecar C, Muntean I. Serum Markers of Brain Injury in Pediatric Patients with Congenital Heart Defects Undergoing Cardiac Surgery: Diagnostic and Prognostic Role. Clin Pract 2023; 13:1253-1265. [PMID: 37887089 PMCID: PMC10605074 DOI: 10.3390/clinpract13050113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/28/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023] Open
Abstract
Introduction: The objectives of this study were to assess the role of neuromarkers like glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), protein S100 (pS100), and neuron-specific enolase (NSE) as diagnostic markers of acute brain injury and also as prognostic markers for short-term neurodevelopmental impairment. Methods: Pediatric patients with congenital heart defects (CHDs) undergoing elective cardiac surgery were included. Neurodevelopmental functioning was assessed preoperatively and 4-6 months postoperatively using the Denver Developmental Screening Test II. Blood samples were collected preoperatively and postoperatively. During surgery, regional cerebral tissue oxygen saturation was monitored using near-infrared spectroscopy (NIRS). Results: Forty-two patients were enrolled and dichotomized into cyanotic and non-cyanotic groups based on peripheric oxygen saturation. Nineteen patients (65.5%) had abnormal developmental scores in the non-cyanotic group and eleven (84.6%) in the cyanotic group. A good diagnostic model was observed between NIRS values and GFAP in the cyanotic CHD group (AUC = 0.7). A good predicting model was observed with GFAP and developmental scores in the cyanotic CHD group (AUC = 0.667). A correlation was found between NSE and developmental quotient scores (r = 0.09, p = 0.046). Conclusions: From all four neuromarkers studied, only GFAP was demonstrated to be a good diagnostic and prognostic factor in cyanotic CHD patients. NSE had only prognostic value.
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Affiliation(s)
- Lacramioara Eliza Chiperi
- Clinic of Pediatric Cardiology, Emergency Institute for Cardiovascular Diseases and Heart Transplant, 540136 Targu Mures, Romania
- Doctoral School, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Adina Huţanu
- Department of Laboratory Medicine, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, 540142 Targu Mures, Romania;
- Laboratory of Humoral Immunology, Center for Advanced Medical and Pharmaceutical Research, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Cristina Tecar
- Department of Neurosciences, Iuliu Hatieganu University of Medicine and Pharmacy, 400129 Cluj-Napoca, Romania
| | - Iolanda Muntean
- Clinic of Pediatric Cardiology, Emergency Institute for Cardiovascular Diseases and Heart Transplant, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, 540142 Targu Mures, Romania;
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25
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Nguyen AM, Saini V, Hinson HE. Blood-Based Biomarkers for Neuroprognostication in Acute Brain Injury. Semin Neurol 2023; 43:689-698. [PMID: 37751855 PMCID: PMC10668565 DOI: 10.1055/s-0043-1775764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Abstract
Acute brain injury causes loss of functionality in patients that often is devastating. Predicting the degree of functional loss and overall prognosis requires a multifaceted approach to help patients, and more so their families, make important decisions regarding plans and goals of care. A variety of blood-based markers have been studied as one aspect of this determination. In this review, we discuss CNS-derived and systemic markers that have been studied for neuroprognostication purposes. We discuss the foundation of each protein, the conditions in which it has been studied, and how the literature has used these markers for interpretation. We also discuss challenges to using each marker in each section as well.
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Affiliation(s)
- Andrew M. Nguyen
- Neurosciences Critical Care Program, Department of Neurology, Oregon Health & Science University, Portland, Oregon
| | - Vishal Saini
- Neurosciences Critical Care Program, Department of Neurology, Oregon Health & Science University, Portland, Oregon
| | - H. E. Hinson
- Department of Neurology, University of California San Francisco, San Francisco, California
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26
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Zimny M, Paździora P, Kocur D, Błaszczyk B, Gendosz de Carrillo D, Baron J, Jędrzejowska-Szypułka H, Rudnik A. Analysis of Serum Markers of Perioperative Brain Injury and Inflammation Associated with Endovascular Treatment of Intracranial Aneurysms: A Preliminary Study. Brain Sci 2023; 13:1308. [PMID: 37759909 PMCID: PMC10526942 DOI: 10.3390/brainsci13091308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/03/2023] [Accepted: 09/09/2023] [Indexed: 09/29/2023] Open
Abstract
Embolization is the preferred method for treating intracranial aneurysms due to its less invasive nature. However, recent findings suggest that even uncomplicated embolization may cause structural damage to the brain through ischemic or inflammatory mechanisms. This study aimed to find possible biomarkers of brain injury and inflammation in patients suffering from intracranial aneurysms who underwent endovascular treatment by measuring serological markers indicating brain damage. The study involved 26 patients who underwent uncomplicated intravascular stenting for unruptured intracranial aneurysms between January 2020 and December 2021. Blood samples were collected before the procedure, at 6-12 h, and at 24 h after the procedure. The following protein biomarkers levels were tested with ELISA: S100B, hNSE, TNF, hsCRP, FABP7, NFL, and GP39. Statistical analysis of the results revealed significant increases in serum levels for the four biomarkers: FABP7-before 0.25 (ng/mL) vs. 6-12 h 0.26 (p = 0.012) and vs. 24 h 0.27 (p < 0.001); GP39-before 0.03 (pg/mL) vs. 6-12 h 0.64 (p = 0.011) and vs. 24 h 0.57 (p = 0.001); hsCRP-before 1.65 (μg/mL) vs. 24 h 4.17 (p = 0.037); NFL-before 0.01 (pg/mL) vs. 6-12 h 3.99 (p = 0.004) and vs. 24 h 1.86 (p = 0.033). These biomarkers are recognized as potential indicators of neurovascular damage and should be monitored in clinical settings. Consequently, serum levels of NFL, GP39, hsCRP, and FABP7 measured before and 24 h after endovascular procedures can serve as important markers for assessing brain damage and indicate avenues for further research on biomarkers of neurovascular injury.
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Affiliation(s)
- Mikołaj Zimny
- Department of Neurosurgery, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
| | - Piotr Paździora
- Department of Neurosurgery, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
| | - Damian Kocur
- Department of Neurosurgery, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
| | - Bartłomiej Błaszczyk
- Department of Neurosurgery, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
| | - Daria Gendosz de Carrillo
- Department of Physiology, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
- Department of Histology and Cell Pathology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
| | - Jan Baron
- Department of Radiodiagnostics, Interventional Radiology and Nuclear Medicine, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
| | | | - Adam Rudnik
- Department of Neurosurgery, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
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27
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Olczak M, Poniatowski ŁA, Siwińska A, Kwiatkowska M. Post-mortem detection of neuronal and astroglial biochemical markers in serum and urine for diagnostics of traumatic brain injury. Int J Legal Med 2023; 137:1441-1452. [PMID: 37272985 DOI: 10.1007/s00414-023-02990-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 03/21/2023] [Indexed: 06/06/2023]
Abstract
Currently available epidemiological data shows that traumatic brain injury (TBI) represents one of the leading causes of death that is associated with medico-legal practice, including forensic autopsy, criminological investigation, and neuropathological examination. Attention focused on TBI research is needed to advance its diagnostics in ante- and post-mortem cases with regard to identification and validation of novel biomarkers. Recently, several markers of neuronal, astroglial, and axonal injury have been explored in various biofluids to assess the clinical origin, progression, severity, and prognosis of TBI. Despite clinical usefulness, understanding their diagnostic accuracy could also potentially help translate them either into forensic or medico-legal practice, or both. The aim of this study was to evaluate post-mortem pro-BDNF, NSE, UCHL1, GFAP, S100B, SPTAN1, NFL, MAPT, and MBP levels in serum and urine in TBI cases. The study was performed using cases (n = 40) of fatal head injury and control cases (n = 20) of sudden death. Serum and urine were collected within ∼ 24 h after death and compared using ELISA test. In our study, we observed the elevated concentration levels of GFAP and MAPT in both serum and urine, elevated concentration levels of S100B and SPTAN1 in serum, and decreased concentration levels of pro-BDNF in serum compared to the control group. The obtained results anticipate the possible implementation of performed assays as an interesting tool for forensic and medico-legal investigations regarding TBI diagnosis where the head injury was not supposed to be the direct cause of death.
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Affiliation(s)
- Mieszko Olczak
- Department of Forensic Medicine, Center for Biostructure Research, Medical University of Warsaw, Oczki 1, 02-007, Warsaw, Poland.
| | - Łukasz A Poniatowski
- Department of Neurosurgery, Dietrich-Bonhoeffer-Klinikum, Salvador-Allende-Straße 30, 17036, Neubrandenburg, Germany
| | - Agnieszka Siwińska
- Department of Forensic Medicine, Center for Biostructure Research, Medical University of Warsaw, Oczki 1, 02-007, Warsaw, Poland
| | - Magdalena Kwiatkowska
- Department of Forensic Medicine, Center for Biostructure Research, Medical University of Warsaw, Oczki 1, 02-007, Warsaw, Poland
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Mansour NO, Elnaem MH, Abdelaziz DH, Barakat M, Dehele IS, Elrggal ME, Abdallah MS. Effects of early adjunctive pharmacotherapy on serum levels of brain injury biomarkers in patients with traumatic brain injury: a systematic review of randomized controlled studies. Front Pharmacol 2023; 14:1185277. [PMID: 37214454 PMCID: PMC10196026 DOI: 10.3389/fphar.2023.1185277] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 04/14/2023] [Indexed: 05/24/2023] Open
Abstract
Objectives: Traumatic brain injury (TBI) is one of the top causes of morbidity and mortality worldwide. The review aimed to discuss and summarize the current evidence on the effectiveness of adjuvant neuroprotective treatments in terms of their effect on brain injury biomarkers in TBI patients. Methods: To identify relevant studies, four scholarly databases, including PubMed, Cochrane, Scopus, and Google Scholar, were systematically searched using predefined search terms. English-language randomized controlled clinical trials reporting changes in brain injury biomarkers, namely, neuron-specific enolase (NSE), glial fibrillary acid protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCHL1) and/or S100 beta (S100 ß), were included. The methodological quality of the included studies was assessed using the Cochrane risk-of-bias tool. Results: A total of eleven studies with eight different therapeutic options were investigated; of them, tetracyclines, metformin, and memantine were discovered to be promising choices that could improve neurological outcomes in TBI patients. The most utilized serum biomarkers were NSE and S100 ß followed by GFAP, while none of the included studies quantified UCHL1. The heterogeneity in injury severity categories and measurement timing may affect the overall evaluation of the clinical efficacy of potential therapies. Therefore, unified measurement protocols are highly warranted to inform clinical decisions. Conclusion: Few therapeutic options showed promising results as an adjuvant to standard care in patients with TBI. Several considerations for future work must be directed towards standardizing monitoring biomarkers. Investigating the pharmacotherapy effectiveness using a multimodal biomarker panel is needed. Finally, employing stratified randomization in future clinical trials concerning potential confounders, including age, trauma severity levels, and type, is crucial to inform clinical decisions. Clinical Trial Registration: [https://www.crd.york.ac.uk/prospero/dis], identifier [CRD42022316327].
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Affiliation(s)
- Noha O. Mansour
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Mohamed Hassan Elnaem
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Malaysia
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, United Kingdom
| | - Doaa H. Abdelaziz
- Pharmacy Practice and Clinical Pharmacy Department, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
| | - Muna Barakat
- Department of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Applied Science Private University, Amman, Jordan
- MEU Research Unit, Middle East University, Amman, Jordan
| | | | | | - Mahmoud S. Abdallah
- Department of Clinical Pharmacy, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt
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Andreou D, Steen NE, Jørgensen KN, Smelror RE, Wedervang-Resell K, Nerland S, Westlye LT, Nærland T, Myhre AM, Joa I, Reitan SMK, Vaaler A, Morken G, Bøen E, Elvsåshagen T, Boye B, Malt UF, Aukrust P, Skrede S, Kroken RA, Johnsen E, Djurovic S, Andreassen OA, Ueland T, Agartz I. Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness. Psychol Med 2023; 53:1479-1488. [PMID: 35387700 PMCID: PMC10009386 DOI: 10.1017/s0033291721003056] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 06/05/2021] [Accepted: 07/13/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation. METHODS We included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV. RESULTS We found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males. CONCLUSION We found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.
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Affiliation(s)
- Dimitrios Andreou
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
| | - Nils Eiel Steen
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital, Oslo, Norway
| | - Kjetil Nordbø Jørgensen
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Runar Elle Smelror
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Kirsten Wedervang-Resell
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Child and Adolescent Mental Health Research Unit, Division of Mental Health and Addiction, Department of Research and Innovation, Oslo University Hospital, Oslo, Norway
| | - Stener Nerland
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
| | - Lars T. Westlye
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
| | - Terje Nærland
- K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway
| | - Anne Margrethe Myhre
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Mental Health and Addiction, Department of Research and Innovation, Oslo University Hospital, Oslo, Norway
| | - Inge Joa
- TIPS – Network for Clinical Research in Psychosis, Stavanger University Hospital, Stavanger, Norway
- Faculty of Health, Network for Medical Sciences, University of Stavanger, Stavanger, Norway
| | - Solveig Merete Klæbo Reitan
- Faculty of Medicine and Health Sciences, Department of Mental Health, NTNU, Trondheim, Norway
- St Olavs Hospital, Department of Mental Health, Trondheim, Norway
| | - Arne Vaaler
- Faculty of Medicine and Health Sciences, Department of Mental Health, NTNU, Trondheim, Norway
- St Olavs Hospital, Department of Mental Health, Trondheim, Norway
| | - Gunnar Morken
- Faculty of Medicine and Health Sciences, Department of Mental Health, NTNU, Trondheim, Norway
- St Olavs Hospital, Department of Mental Health, Trondheim, Norway
| | - Erlend Bøen
- Psychosomatic and C-L Psychiatry, Adult, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
| | - Torbjørn Elvsåshagen
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital, Oslo, Norway
- Department of Neurology, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Birgitte Boye
- Psychosomatic and C-L Psychiatry, Adult, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
- Department of Behavioural Medicine, University of Oslo, Oslo, Norway
| | - Ulrik Fredrik Malt
- Department of Neurology, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Pål Aukrust
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Silje Skrede
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
| | - Rune Andreas Kroken
- Division of Psychiatry, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Haukeland University Hospital, Bergen, Norway
| | - Erik Johnsen
- Division of Psychiatry, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Norwegian Centre for Mental Disorders Research (NORMENT), Haukeland University Hospital, Bergen, Norway
| | - Srdjan Djurovic
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- Department of Clinical Science, Norwegian Centre for Mental Disorders Research (NORMENT), University of Bergen, Bergen, Norway
| | - Ole A. Andreassen
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research (NORMENT), Oslo University Hospital, Oslo, Norway
| | - Thor Ueland
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Ingrid Agartz
- Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
- Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
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Stacey BS, Hoiland RL, Caldwell HG, Howe CA, Vermeulen T, Tymko MM, Vizcardo‐Galindo GA, Bermudez D, Figueroa‐Mujíica RJ, Gasho C, Tuaillon E, Hirtz C, Lehmann S, Marchi N, Tsukamoto H, Villafuerte FC, Ainslie PN, Bailey DM. Lifelong exposure to high-altitude hypoxia in humans is associated with improved redox homeostasis and structural-functional adaptations of the neurovascular unit. J Physiol 2023; 601:1095-1120. [PMID: 36633375 PMCID: PMC10952731 DOI: 10.1113/jp283362] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 12/20/2022] [Indexed: 01/13/2023] Open
Abstract
High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia.
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Affiliation(s)
- Benjamin S. Stacey
- Neurovascular Research Laboratory, Faculty of Life Sciences and EducationUniversity of South WalesPontypriddUK
| | - Ryan L. Hoiland
- Department of Anaesthesiology, Pharmacology and Therapeutics, Vancouver General HospitalUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Department of Cellular and Physiological Sciences, Faculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Hannah G. Caldwell
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
| | - Connor A. Howe
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
| | - Tyler Vermeulen
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
| | - Michael M. Tymko
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
- Faculty of Kinesiology, Sport, and RecreationUniversity of AlbertaEdmontonAlbertaCanada
- Department of Medicine, Faculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Gustavo A. Vizcardo‐Galindo
- Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y FilosofíaUniversidad Peruana Cayetano HerediaLima 31Peru
| | - Daniella Bermudez
- Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y FilosofíaUniversidad Peruana Cayetano HerediaLima 31Peru
| | - Rómulo J. Figueroa‐Mujíica
- Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y FilosofíaUniversidad Peruana Cayetano HerediaLima 31Peru
| | - Christopher Gasho
- Division of Pulmonary and Critical CareLoma Linda University School of MedicineLoma LindaCAUSA
| | - Edouard Tuaillon
- Department of Infectious DiseasesUniversity of MontpellierMontpellierFrance
| | - Christophe Hirtz
- LBPC‐PPCUniversité de Montpellier, IRMB CHU de Montpellier, INM INSERMMontpellierFrance
| | - Sylvain Lehmann
- LBPC‐PPCUniversité de Montpellier, IRMB CHU de Montpellier, INM INSERMMontpellierFrance
| | - Nicola Marchi
- Laboratory of Cerebrovascular and Glia Research, Department of Neuroscience, Institute of Functional GenomicsUniversity of MontpellierMontpellierFrance
| | - Hayato Tsukamoto
- Faculty of Sport and Health ScienceRitsumeikan UniversityKusatsuShigaJapan
| | - Francisco C. Villafuerte
- Laboratorio de Fisiología Comparada, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias y FilosofíaUniversidad Peruana Cayetano HerediaLima 31Peru
| | - Philip N. Ainslie
- Neurovascular Research Laboratory, Faculty of Life Sciences and EducationUniversity of South WalesPontypriddUK
- Centre for Heart, Lung and Vascular HealthUniversity of British Columbia‐Okanagan CampusKelownaBritish ColumbiaCanada
| | - Damian M. Bailey
- Neurovascular Research Laboratory, Faculty of Life Sciences and EducationUniversity of South WalesPontypriddUK
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Kim HB, Yang JH, Lee YH. Are serial neuron-specific enolase levels associated with neurologic outcome of ECPR patients: A retrospective multicenter observational study. Am J Emerg Med 2023; 69:58-64. [PMID: 37060630 DOI: 10.1016/j.ajem.2023.03.047] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/19/2023] [Accepted: 03/22/2023] [Indexed: 04/03/2023] Open
Abstract
AIM OF THE STUDY This study aims to evaluate whether neuron-specific enolase (NSE) level at 48 h after extracorporeal cardiopulmonary resuscitation (ECPR) is associated with neurologic outcomes at 6 months after hospital discharge. METHODS This was a retrospective, multicenter, observational study of adult patients who received ECPR between May 2010 and December 2016. In the two hospitals involved in this study, NSE measurements were a routine part of the protocol for patients who received ECPR. Serial NSE levels were measured in all patients with ECPR. NSE levels were measured 24, 48, and 72 h after ECPR. The primary outcome was Cerebral Performance Categories (CPC) scale at 6 months after hospital discharge according to NSE levels at 48 h after ECPR. RESULTS At follow-up 6 months after hospital discharge, favorable neurologic outcomes of CPC 1 or 2 were observed in 9 (36.0%) of the 25 patients, and poor neurologic outcomes of CPC 3, 4, or 5 were observed in 16 (64%) patients. NSE levels at 24 h in the favorable and poor neurologic outcome groups were 58.3 (52.5-73.2) μg/L and 64.2 (37.9-89.8) μg/L, respectively (p = 0.95). NSE levels at 48 h in the favorable and poor neurologic outcome groups were 52.1 (22.3-64.9) μg/L and 302.0 (62.8-360.2) μg/L, respectively (p = 0.01). NSE levels at 72 h were 37.2 (12.5-53.2) μg/L and 240.9 (75.3-370.0) μg/L, respectively (p < 0.01). In receiver operating characteristic (ROC) curve analysis, as the predictor of poor outcome, the optimal cut-off value for NSE level at 48 h was 140.5 μg/L, and the area under the curve (AUC) was 0.844 (p < 0.01). The optimal cut-off NSE level at 72 h was 53.2 μg/L, and the AUC was 0.897 (p < 0.01). CONCLUSIONS NSE level at 72 h displayed the highest association with neurologic outcome after ECPR, and NSE level at 48 h was also associated with neurologic outcome after ECPR.
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Chiperi LE, Tecar C, Toganel R. Neuromarkers which can predict neurodevelopmental impairment among children with congenital heart defects after cardiac surgery: A systematic literature review. Dev Neurorehabil 2023; 26:206-215. [PMID: 36710475 DOI: 10.1080/17518423.2023.2166618] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The aim of this systematic literature review was to assess the data regarding neuromarkers used to evaluate the impact of cardiovascular surgery on neurodevelopmental pattern of children with congenital heart defects. A systematic search was performed on PubMed and Google Scholar databases. Out of 713 publications screened, 10 studies (471 patients) met the inclusion criteria. The included studies were coded on several variables: number and heterogeneity of patients (age, congenital heart defects), exclusion of patients with conditions that predispose to neurological impairment, neuroimaging workup pre- and post-surgery, neurodevelopmental assessment, interventions (part of a different study), and follow-up period. Results were reported according to PRISMA guidelines. Findings include: neuron-specific enolase and brain-derived neurotrophic factor are not reliable neuromarkers, for protein S100B different results were reported, for activin A there is lack of evidence, and glial fibrillary acidic protein could represent a reliable neuromarker for acute brain-injury. Directions for future research are discussed.
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Affiliation(s)
- Lacramioara Eliza Chiperi
- Department of Pediatric Cardiology, Emergency Institute for Cardiovascular Diseases and Heart Transplant, Targu Mures, Romania.,Doctoral School of I.O.S.U.D., George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania
| | - Cristina Tecar
- Department of Neurosciences, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Rodica Toganel
- Department of Pediatrics, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania
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Long-Term Outcomes among Patients with Prolonged Disorders of Consciousness. Brain Sci 2023; 13:brainsci13020194. [PMID: 36831737 PMCID: PMC9954359 DOI: 10.3390/brainsci13020194] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/07/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023] Open
Abstract
PURPOSE To evaluate the long-term survival and functional outcomes of patients with prolonged disorders of consciousness (pDoC) 1-8 years after brain injuries. METHODS Retrospective study to assess the long-term survival and functional outcomes of patients with pDoC was conducted. We performed Cox regression and multivariate logistic regression to calculate hazard ratios (HRs) for the outcome of survival and to identify risk factors of the functional outcome. RESULTS We recruited 154 patients with pDoC. The duration of follow-up from disease onset was 1-8 years. The median age was 46 years (IQR, 32-59), and 65.6% (n = 101) of them were men. During the follow-up period, one hundred and ten patients (71.4%) survived; among them, 52 patients had a good outcome. From the overall survival curve, the 1-, 3-, and 8-year survival rates of patients were about 80.5%, 72.0%, and 69.7%, respectively. Cox regression analysis revealed a significant association between the lower APACHE II score (p = 0.005) (cut-off score ≥ 18) and the presence of sleep spindles (p = 0.001) with survival. Logistic regression analysis demonstrated a higher CRS-R score (cut-off score ≥ 7), and presence of sleep spindles were related to a favorable outcome among patients with pDoC. CONCLUSIONS Sleep spindles are correlated with both long-term survival and long-term functional outcome in pDoC patients.
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Harris G, Rickard JJS, Butt G, Kelleher L, Blanch RJ, Cooper J, Oppenheimer PG. Review: Emerging Eye-Based Diagnostic Technologies for Traumatic Brain Injury. IEEE Rev Biomed Eng 2023; 16:530-559. [PMID: 35320105 PMCID: PMC9888755 DOI: 10.1109/rbme.2022.3161352] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 02/11/2022] [Accepted: 03/15/2022] [Indexed: 11/06/2022]
Abstract
The study of ocular manifestations of neurodegenerative disorders, Oculomics, is a growing field of investigation for early diagnostics, enabling structural and chemical biomarkers to be monitored overtime to predict prognosis. Traumatic brain injury (TBI) triggers a cascade of events harmful to the brain, which can lead to neurodegeneration. TBI, termed the "silent epidemic" is becoming a leading cause of death and disability worldwide. There is currently no effective diagnostic tool for TBI, and yet, early-intervention is known to considerably shorten hospital stays, improve outcomes, fasten neurological recovery and lower mortality rates, highlighting the unmet need for techniques capable of rapid and accurate point-of-care diagnostics, implemented in the earliest stages. This review focuses on the latest advances in the main neuropathophysiological responses and the achievements and shortfalls of TBI diagnostic methods. Validated and emerging TBI-indicative biomarkers are outlined and linked to ocular neuro-disorders. Methods detecting structural and chemical ocular responses to TBI are categorised along with prospective chemical and physical sensing techniques. Particular attention is drawn to the potential of Raman spectroscopy as a non-invasive sensing of neurological molecular signatures in the ocular projections of the brain, laying the platform for the first tangible path towards alternative point-of-care diagnostic technologies for TBI.
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Affiliation(s)
- Georgia Harris
- School of Chemical Engineering, Advanced Nanomaterials Structures and Applications Laboratories, College of Engineering and Physical SciencesUniversity of BirminghamB15 2TTBirminghamU.K.
| | - Jonathan James Stanley Rickard
- School of Chemical Engineering, Advanced Nanomaterials Structures and Applications Laboratories, College of Engineering and Physical SciencesUniversity of BirminghamB15 2TTBirminghamU.K.
- Department of Physics, Cavendish LaboratoryUniversity of CambridgeCB3 0HECambridgeU.K.
| | - Gibran Butt
- Ophthalmology DepartmentUniversity Hospitals Birmingham NHS Foundation TrustB15 2THBirminghamU.K.
| | - Liam Kelleher
- School of Chemical Engineering, Advanced Nanomaterials Structures and Applications Laboratories, College of Engineering and Physical SciencesUniversity of BirminghamB15 2TTBirminghamU.K.
| | - Richard James Blanch
- Department of Military Surgery and TraumaRoyal Centre for Defence MedicineB15 2THBirminghamU.K.
- Neuroscience and Ophthalmology, Department of Ophthalmology, University Hospitals Birmingham NHS Foundation TrustcBirminghamU.K.
| | - Jonathan Cooper
- School of Biomedical EngineeringUniversity of GlasgowG12 8LTGlasgowU.K.
| | - Pola Goldberg Oppenheimer
- School of Chemical Engineering, Advanced Nanomaterials Structures and Applications Laboratories, College of Engineering and Physical SciencesUniversity of BirminghamB15 2TTBirminghamU.K.
- Healthcare Technologies Institute, Institute of Translational MedicineB15 2THBirminghamU.K.
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Lin IH, Kamnaksh A, Aniceto R, McCullough J, Bekdash R, Eklund M, Ghatan PH, Risling M, Svensson M, Bellander BM, Nelson DW, Thelin EP, Agoston DV. Time-Dependent Changes in the Biofluid Levels of Neural Injury Markers in Severe Traumatic Brain Injury Patients-Cerebrospinal Fluid and Cerebral Microdialysates: A Longitudinal Prospective Pilot Study. Neurotrauma Rep 2023; 4:107-117. [PMID: 36895820 PMCID: PMC9989523 DOI: 10.1089/neur.2022.0076] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023] Open
Abstract
Monitoring protein biomarker levels in the cerebrospinal fluid (CSF) can help assess injury severity and outcome after traumatic brain injury (TBI). Determining injury-induced changes in the proteome of brain extracellular fluid (bECF) can more closely reflect changes in the brain parenchyma, but bECF is not routinely available. The aim of this pilot study was to compare time-dependent changes of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), total Tau, and phosphorylated Tau (p-Tau) levels in matching CSF and bECF samples collected at 1, 3, and 5 days post-injury from severe TBI patients (n = 7; GCS 3-8) using microcapillary-based western analysis. We found that time-dependent changes in CSF and bECF levels were most pronounced for S100B and NSE, but there was substantial patient-to-patient variability. Importantly, the temporal pattern of biomarker changes in CSF and bECF samples showed similar trends. We also detected two different immunoreactive forms of S100B in both CSF and bECF samples, but the contribution of the different immunoreactive forms to total immunoreactivity varied from patient to patient and time point to time point. Our study is limited, but it illustrates the value of both quantitative and qualitative analysis of protein biomarkers and the importance of serial sampling for biofluid analysis after severe TBI.
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Affiliation(s)
- I-Hsuan Lin
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Alaa Kamnaksh
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Roxanne Aniceto
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Jesse McCullough
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Ramsey Bekdash
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Michael Eklund
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
| | - Per Hamid Ghatan
- Department of Neuroscience, Uppsala University Hospital, Uppsala, Sweden
| | - Mårten Risling
- Department of Neuroscience, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Mikael Svensson
- Department of Clinical Neuroscience, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.,Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
| | - Bo-Michael Bellander
- Department of Clinical Neuroscience, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.,Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
| | - David W Nelson
- Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.,Section of Perioperative Medicine and Intensive Care, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Eric Peter Thelin
- Department of Clinical Neuroscience, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.,Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
| | - Denes V Agoston
- Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, Maryland, USA
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Pandey V, Shukla D, Nirmal S, Devi BI, Christopher R. Biomarkers in Traumatic Brain Injuries: Narrative Review. INDIAN JOURNAL OF NEUROTRAUMA 2022. [DOI: 10.1055/s-0042-1759853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AbstractTraumatic brain injury (TBI) is a multistep interaction of brain antigens, cytokine-mediated humeral, and cellular immune reactions. Because of the limitations of clinical and radiological evaluation in TBI, there has been a considerable advancement toward the need for developing biomarkers that can predict the severity of TBI. Blood-based brain biomarkers hold the potential to predict the absence of intracranial injury and thus decrease unnecessary brain computed tomographic scanning. Various biomarkers have been studied that detects neuronal, axonal, and blood–brain barrier integrity. Biomarkers are still under investigation and hold promise in the future evaluation of TBI patients. They can be used for grading as well as a prognostication of head injury.
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Affiliation(s)
- Vishram Pandey
- Department of Neurosurgery, National Institute of Mental Health and Neurosciences, NIMHANS, Bangalore, Karnataka, India
| | - Dhaval Shukla
- Department of Neurosurgery, National Institute of Mental Health and Neurosciences, NIMHANS, Bangalore, Karnataka, India
| | - Shubham Nirmal
- Department of Neurosurgery, National Institute of Mental Health and Neurosciences, NIMHANS, Bangalore, Karnataka, India
| | - Bhagavatula Indira Devi
- Department of Neurosurgery, National Institute of Mental Health and Neurosciences, NIMHANS, Bangalore, Karnataka, India
| | - Rita Christopher
- Department of Neurosurgery, National Institute of Mental Health and Neurosciences, NIMHANS, Bangalore, Karnataka, India
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COMPARATIVE EVALUATION AND PROGNOSTIC UTILITY OF NEURONAL INJURY BIOMARKERS IN COVID-19 PATIENTS: A PROSPECTIVE STUDY. Shock 2022; 58:507-513. [PMID: 36548642 DOI: 10.1097/shk.0000000000002017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
ABSTRACT Background : COVID-19 disease severity markers include mostly molecules related to not only tissue perfusion, inflammation, and thrombosis, but also biomarkers of neural injury. Clinical and basic research has demonstrated that SARS-COV-2 affects the central nervous system. The aims of the present study were to investigate the role of neural injury biomarkers and to compare them with inflammatory markers in their predictive ability of mortality. Methods : We conducted a prospective observational study in critically ill patients with COVID-19 and in a cohort of patients with moderate/severe disease. S100b, neuron-specific enolase (NSE), and inflammatory markers, including soluble urokinase plasminogen activator receptor (suPAR), were measured on intensive care unit or ward admission, respectively. Statistical comparisons between patient groups were performed for all biomarkers under investigation. Correlations between different biomarkers were tested with Spearman correlation coefficient. Receiver operating characteristic curves were plotted using mortality as the classification variable and the biomarker levels on admission as the prognostic variables. Results : A total of 70 patients with COVID-19 were included in the final analysis. Of all studied biomarkers, s100b had the best predictive ability for death in the intensive care unit, with an area under the curve of 0.73 (0.61-0.83), P = 0.0003. S100b levels correlated with NSE, interleukin (IL)-8, and IL-10 (0.27 < rs < 0.37, P < 0.05), and tended to correlate with suPAR ( rs = 0.26, P = 0.05), but not with the vasopressor dose ( P = 0.62). Conclusion : Among the investigated biomarkers, s100b demonstrated the best predictive ability for death in COVID-19 patients. The overall biomarker profile of the patients implies direct involvement of the nervous system by the novel coronavirus.
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Pediatric delirium is associated with increased brain injury marker levels in cardiac surgery patients. Sci Rep 2022; 12:18681. [PMID: 36333387 PMCID: PMC9636141 DOI: 10.1038/s41598-022-22702-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
Despite global consensus on the importance of screening pediatric delirium, correlations between pediatric delirium during acute brain injury and adult delirium are unclear. Therefore, we hypothesized that similar pediatric biomarkers reflect acute brain injury as in adult delirium. We observed pediatric cardiac surgery patients from neonatal age to 18 years, who were admitted to our pediatric intensive care unit after cardiovascular operations between October 2019 to June 2020, up to post-operative day 3 (4 days total). We recorded age, sex, risk score (Risk Adjustment in Congenital Heart Surgery [RACHS-1]), midazolam/dexmedetomidine/fentanyl dosage, and pediatric Sequential Organ Failure Assessment (pSOFA). Richmond Agitation-Sedation Scale (RASS), Cornell Assessment of Pediatric Delirium (CAPD), Face, Leg, Activity, Consolability (FLACC) behavioral scale, and Withdrawal Assessment Tool (WAT-1) scales were used and serum sampling for neuron specific enolase (NSE) was conducted. Consciousness status was considered hierarchical (coma > delirium > normal) and associations between conscious status and NSE were conducted by hierarchical Bayesian modeling. We analyzed 134 data points from 40 patients (median age 12 months). In the multi-regression model, NSE was positively associated with coma [posterior odds ratio (OR) = 1.1, 95% credible interval (CrI) 1.01-1.19] while pSOFA [posterior OR = 1.63, 95% CrI 1.17-2.5], midazolam [posterior OR = 1.02, 95% CrI 1.01-1.04], and dexmedetomidine [posterior OR = 9.52, 95% CrI 1.02-108.85] were also associated. We also evaluated consciousness state probability at each NSE concentration and confirmed both that consciousness was hierarchically sorted and CAPD scores were also associated with NSE [posterior OR = 1.32, 95% CrI 1.09-1.58]. "Eye contact" (r = 0.55) was the most correlated component with NSE within the pain, withdrawal syndrome, and PD items. PD within the hierarchy of consciousness (coma, delirium, normal) and CAPD scores are associated with brain injury marker levels. Using pediatric delirium assessment tools for monitoring brain injury, especially eye contact, is a reliable method for observing PD.
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Mafuika SN, Naicker T, Harrichandparsad R, Lazarus L. The potential of serum S100 calcium-binding protein B and glial fibrillary acidic protein as biomarkers for traumatic brain injury. TRANSLATIONAL RESEARCH IN ANATOMY 2022. [DOI: 10.1016/j.tria.2022.100228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Abstract
OBJECTIVE S100B is a glial cell protein with bimodal function. In low concentrations, it exerts neurotrophic effects, but higher levels reflect neuronal distress. Recent research suggests that this molecule may be a biomarker of response to electroconvulsive therapy (ECT). We examined the effect of ECT on serum S100B and its utility as 1) a biomarker of a depressive state and 2) a predictor of ECT response. We also wanted to ensure that ECT does not cause a marked serum S100B elevation, indicating neural distress. METHODS We measured serum S100B in 22 in-patients treated with ECT due to depression. Depression severity was assessed using 17-item Hamilton Rating Scale for Depression (HAMD-17). The data were collected before an ECT series, within 1 week after the series (post-ECT), and at a 6-month follow-up. Changes in serum S100B and clinical outcomes were tested using a linear mixed model. A relationship between serum S100B and the clinical outcomes was examined using Spearman's and partial correlation. RESULTS Serum S100B did not change significantly immediately after an ECT series or 6 months later. The post-ECT serum S100B change was not associated with the clinical effect (rho = 0.14, n = 22, p = 0.54). The baseline serum S100B did not predict the clinical effect when controlling for age (r = 0.02, n = 22, df = 19, p = 0.92). CONCLUSION The study neither supports serum S100B as a state marker of depression nor a predictor of ECT response. No evidence for ECT-related neural distress was found.
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MATYAR S, AÇIKALIN A, DİŞEL R, GORUROGLU OZTURK O, DAĞLIOĞLU G, AKPINAR O. Hiponatremili hastalarda serum nöron spesifik enolaz düzeyleri ile beyin hasarı arasındaki ilişki. CUKUROVA MEDICAL JOURNAL 2022. [DOI: 10.17826/cumj.1124909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Amaç: Bu çalışmada hiponatremili hastalarda serum nöron spesifik enolazın santral sinir sistemi hasarını öngörmesi ve klinik gidiş üzerindeki etkilerini araştırmayı amaçladık.
Gereç ve Yöntem: Bu prospektif çalışmada, serum sodyum seviyeleri 135 mEq/L'nin altında olan 75 yetişkin hasta değerlendirildi. Hastalar serum nöron spesifik enolaz düzeylerine göre gruplandırıldı (grup 1 ≤ 17.0 ng/mL ve grup 2 > 17.0 ng/mL). Gruplar demografik ve laboratuvar verilerine göre karşılaştırıldı.
Bulgular: Grup 2 hastalarında hipertansiyon, kalp yetmezliği ve bilinç kaybı insidansı anlamlı olarak daha yüksekti. Yüksek nöron spesifik enolaz seviyeleri, daha düşük serum sodyum seviyeleri ile ilişkiliydi. Ortalama sodyum seviyeleri grup 1 ve 2'de sırasıyla 129.5 ± 4.3 mEq/L ve 126 ± 4.5 mEq/L idi. Grup 2'deki hastalardan (n = 45), bilinç kaybı olan (düşük Glasgow Koma Skalası skorları) (GKS
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Abstract
Research into TBI biomarkers has accelerated rapidly in the past decade owing to the heterogeneous nature of TBI pathologies and management, which pose challenges to TBI evaluation, management, and prognosis. TBI biomarker proteins resulting from axonal, neuronal, or glial cell injuries are widely used and have been extensively studied. However, they might not pass the blood-brain barrier with sufficient amounts to be detected in peripheral blood specimens, and further might not be detectable in the cerebrospinal fluid owing to flow limitations triggered by the injury itself. Despite the advances in TBI research, there is an unmet clinical need to develop and identify novel TBI biomarkers that entirely correlate with TBI pathologies on the molecular level, including mild TBI, and further enable physicians to predict patient outcomes and allow researchers to test neuroprotective agents to limit the extents of injury. Although the extracellular vesicles have been identified and studied long ago, they have recently been revisited and repurposed as potential TBI biomarkers that overcome the many limitations of the traditional blood and CSF assays. Animal and human experiments demonstrated the accuracy of several types of exosomes and miRNAs in detecting mild, moderate, and severe TBI. In this paper, we provide a comprehensive review of the traditional TBI biomarkers that are helpful in clinical practice. Also, we highlight the emerging roles of exosomes and miRNA being the promising candidates under investigation of current research.
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The prognostic significance of biomarkers in cerebrospinal fluid following severe traumatic brain injury: a systematic review and meta-analysis. Neurosurg Rev 2022; 45:2547-2564. [PMID: 35419643 DOI: 10.1007/s10143-022-01786-4] [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: 11/09/2021] [Revised: 03/04/2022] [Accepted: 04/04/2022] [Indexed: 10/18/2022]
Abstract
After severe traumatic brain injury (sTBI) proteins, neurotrophic factors and inflammatory markers are released into the biofluids. This review and meta-analysis searched the literature for prognostic candidate cerebrospinal fluid markers and their relation to sTBI patient outcome. A systematic search of the literature was carried out across PubMed, EMBASE, PubMed Central (PMC), and Cochrane Central Library. Biomarker concentrations were related to the Glasgow Outcome Scale dichotomized into favorable and unfavorable outcomes. When a biomarker was reported in ≥ 3 studies, it was included in meta-analysis. The search returned 1527 articles. After full-text analysis, 54 articles were included, 34 from the search, and 20 from the reference lists. Of 9 biomarkers, 8 were significantly different compared to controls (IL-4, IL-6, IL-8, IL-10, TNFα, sFas, BDNF, and cortisol). Of these, 5 were significantly increased in sTBI patients with unfavorable outcome (IL-6, IL-8, IL-10, TNFα, and cortisol), compared to patients with favorable outcome. This review demonstrated a correlation between 5 biomarkers and clinical outcome in sTBI patients. The paucity of included studies, however, makes it difficult to extrapolate further on this finding.
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Ţolescu RŞ, Zorilă MV, Kamal KC, Marinaş MC, Zorilă GL, Mureşan CO, Zăvoi RE, Oprica AC, Florou C, Mogoantă L, Mitroi G. Histological and immunohistochemical study of brain damage in traumatic brain injuries in children, depending on the survival period. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2022; 63:169-179. [PMID: 36074681 PMCID: PMC9593125 DOI: 10.47162/rjme.63.1.18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/05/2022] [Indexed: 06/15/2023]
Abstract
Numerous studies showed that, at present, traumatic brain injury (TBI) is one of the main causes of death in young adults, but also a main cause of disabilities at all ages. For these reasons, TBI are continuously investigated. In our study, we evaluated the histopathological (HP) and immunohistochemical (IHC) changes that occurred in the brain in underage patients after a severe TBI depending on the survival period. We histopathologically and immunohistochemically analyzed a number of 22 cases of children, deceased in Dolj County, Romania, following some severe TBI, undergoing autopsy within the Institute of Forensic Medicine in Craiova between 2015-2020. Patients were divided into three groups depending on the survival period, namely: (i) patients who died during the first 24 hours of the accident; (ii) patients who died after seven days of survival; (iii) patients who died after 15 days of survival. Microscopic examinations of the brain fragments, collected during the necropsy examination, showed that the traumatic agent caused primary injuries in all brain structures (cerebral parenchyma, meninges, blood vessels). However, HP injuries ranged in size and intensity from one area to another of the brain. In patients with a longer survival period, there was observed the presence of smaller primary injuries and larger secondary injuries. There was also observed a growth in the number of meningo-cerebral microscopic injuries, depending on the increase of the survival period.
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Affiliation(s)
- Răzvan Ştefan Ţolescu
- Department of Forensic Medicine, University of Medicine and Pharmacy of Craiova, Romania
| | - Marian Valentin Zorilă
- Department of Forensic Medicine, University of Medicine and Pharmacy of Craiova, Romania
| | | | | | - George Lucian Zorilă
- Department of Obstetrics and Gynecology, University of Medicine and Pharmacy of Craiova, Romania
| | - Camelia Oana Mureşan
- Department of Legal Medicine, Bioethics, Deontology and Medical Law, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Roxana Eugenia Zăvoi
- Department of Forensic Medicine, University of Medicine and Pharmacy of Craiova, Romania
| | | | - Charoula Florou
- Department of Forensic Medicine, General University Hospital of Larissa, Greece
| | - Laurenţiu Mogoantă
- Department of Histology, University of Medicine and Pharmacy of Craiova, Romania
| | - George Mitroi
- Department of Urology, University of Medicine and Pharmacy of Craiova, Romania
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Ma J, Wang J, Deng K, Gao Y, Xiao W, Hou J, Jiang C, Li J, Yu B. The Effect of MaxiK Channel on Regulating the Activation of NLRP3 Inflammasome in Rats of Blast-induced Traumatic Brain Injury. Neuroscience 2021; 482:132-142. [PMID: 34923036 DOI: 10.1016/j.neuroscience.2021.12.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 12/12/2021] [Accepted: 12/13/2021] [Indexed: 10/19/2022]
Abstract
Abundant findings including our previous work proved that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome exerts a key role in the process of neuroinflammation following blast-induced traumatic brain injury (bTBI). The opening of potassium channels leads to low K+ environment in cells, which appears to be an essential requirement for NLRP3 inflammasome activation. Notably, MaxiK (BK) channel is significant for K+ transport. The present study is aim to investigate the potential role of MaxiK in the activation of NLRP3 and to evaluate whether MaxiK channel blocker paxilline could confer beneficial effects on attenuating the severity of bTBI in rats. Rats were randomly assigned into five groups (n = 8). MaxiK channel expression was measured in bTBI rats. The effect of paxilline on the expression of NLRP3 inflammasome, the level of inflammatory cytokines, brain injury biomarkers in serum and brain edema were also evaluated in bTBI rats. The results showed that the expression of MaxiK was elevated significantly in the cerebral cortex of bTBI rats. The treatment of MaxiK channel blocker paxilline suppressed the NLRP3 inflammasome expression substantially. In addition, paxilline could also decrease the level of pro-inflammatory cytokines and the biomarkers of brain injury and alleviate brain edema of bTBI rats. Our findings have revealed that MaxiK channel might be involved in the process of neuroinflammation of bTBI. Paxilline could depress neuro-inflammation response and alleviate brain injury by blocking MaxiK channel and subsequently inhibition of NLRP3 inflammasome activation.
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Affiliation(s)
- Jie Ma
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China.
| | - Junrui Wang
- Department of Orthopaedics, Chengdu Second People's Hospital, Chengdu, Sichuan, PR China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing, PR China
| | - Kaiwen Deng
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China
| | - Yu Gao
- Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Wenjing Xiao
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China
| | - Jun Hou
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China
| | - Changqing Jiang
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China
| | - Jing Li
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China
| | - Botao Yu
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu, Sichuan, PR China.
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Elia A, Woods DR, Barlow MJ, Lees MJ, O'Hara JP. Cerebral, cardiac and skeletal muscle stress associated with a series of static and dynamic apnoeas. Scand J Med Sci Sports 2021; 32:233-241. [PMID: 34597427 DOI: 10.1111/sms.14067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 09/21/2021] [Accepted: 09/28/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE This study sought to explore, for the first time, the effects of repeated maximal static and dynamic apnoeic attempts on the physiological milieu by assessing cerebral, cardiac and striatal muscle stress-related biomarkers in a group of elite breath-hold divers (EBHD). METHODS Sixteen healthy males were recruited (EBHD = 8; controls = 8). On two separate occasions, EBHD performed two sets of five repeated maximal static apnoeas (STA) or five repeated maximal dynamic apnoeas (DYN). Controls performed a static eupnoeic protocol to negate any effects of water immersion and diurnal variation on haematology (CTL). Venous blood samples were drawn at 30, 90, and 180 min after each protocol to determine S100β, neuron-specific enolase (NSE), myoglobin, and high sensitivity cardiac troponin T (hscTNT) concentrations. RESULTS S100β and myoglobin concentrations were elevated following both apnoeic interventions (p < 0.001; p ≤ 0.028, respectively) but not after CTL (p ≥ 0.348). S100β increased from baseline (0.024 ± 0.005 µg/L) at 30 (STA, +149%, p < 0.001; DYN, +166%, p < 0.001) and 90 min (STA, +129%, p < 0.001; DYN, +132%, p = 0.008) following the last apnoeic repetition. Myoglobin was higher than baseline (22.3 ± 2.7 ng/ml) at 30 (+42%, p = 0.04), 90 (+64%, p < 0.001) and 180 min (+49%, p = 0.013) post-STA and at 90 min (+63%, p = 0.016) post-DYN. Post-apnoeic S100β and myoglobin concentrations were higher than CTL (STA, p < 0.001; DYN, p ≤ 0.004). NSE and hscTNT did not change from basal concentrations after the apnoeic (p ≥ 0.146) nor following the eupnoeic (p ≥ 0.553) intervention. CONCLUSIONS This study suggests that a series of repeated maximal static and dynamic apnoeas transiently disrupt the blood-brain barrier and instigate muscle injury but do not induce neuronal-parenchymal damage or myocardial damage.
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Affiliation(s)
- Antonis Elia
- Division of Environmental Physiology, School of Chemistry, Bioengineering and Health, KTH Royal Institute of Technology, Stockholm, Sweden.,Carnegie School of Sport, Leeds Beckett University, Leeds, UK
| | - David R Woods
- Carnegie School of Sport, Leeds Beckett University, Leeds, UK.,Research and Clinical Innovation, Royal Centre for Defence Medicine, Birmingham, UK
| | | | - Matthew J Lees
- Faculty of Kinesiology and Physical Education, University of Toronto, Toronto, Ontario, Canada
| | - John P O'Hara
- Carnegie School of Sport, Leeds Beckett University, Leeds, UK
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Ganeshalingham A, Beca J. Serum biomarkers in severe paediatric traumatic brain injury-a narrative review. Transl Pediatr 2021; 10:2720-2737. [PMID: 34765496 PMCID: PMC8578762 DOI: 10.21037/tp-20-386] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 05/14/2021] [Indexed: 11/22/2022] Open
Abstract
Severe traumatic brain injury continues to present complex management and prediction challenges for the clinician. While there is some evidence that better systems of care can improve outcome, multiple multi-centre randomised controlled trials of specific therapies have consistently failed to show benefit. In addition, clinicians are challenged in attempting to accurately predict which children will recover well and which children will have severe and persisting neurocognitive deficits. Traumatic brain injury is vastly heterogeneous and so it is not surprising that one therapy or approach, when applied to a mixed cohort of children in a clinical trial setting, has yielded disappointing results. Children with severe traumatic brain injury have vastly different brain injury pathologies of widely varying severity, in any number of anatomical locations at what may be disparate stages of brain development. This heterogeneity may also explain why clinicians are unable to accurately predict outcome. Biomarkers are objective molecular signatures of injury that are released following traumatic brain injury and may represent a way of unifying the heterogeneity of traumatic brain injury into a single biosignature. Biomarkers hold promise to diagnose brain injury severity, guide intervention selection for clinical trials, or provide vital prognostic information so that early intervention and rehabilitation can be planned much earlier in the course of a child's recovery. Serum S100B and serum NSE levels show promise as a diagnostic tool with biomarker levels significantly higher in children with severe TBI including children with inflicted and non-inflicted head injury. Serum S100B and serum NSE also show promise as a predictor of neurodevelopmental outcome. The role of biomarkers in traumatic brain injury is an evolving field with the potential for clinical application within the next few years.
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Affiliation(s)
| | - John Beca
- Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand
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Raghu VK, Horvat CM, Kochanek PM, Fink EL, Clark RSB, Benos PV, Au AK. Neurological Complications Acquired During Pediatric Critical Illness: Exploratory "Mixed Graphical Modeling" Analysis Using Serum Biomarker Levels. Pediatr Crit Care Med 2021; 22:906-914. [PMID: 34054117 PMCID: PMC8490289 DOI: 10.1097/pcc.0000000000002776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Neurologic complications, consisting of the acute development of a neurologic disorder, that is, not present at admission but develops during the course of illness, can be difficult to detect in the PICU due to sedation, neuromuscular blockade, and young age. We evaluated the direct relationships of serum biomarkers and clinical variables to the development of neurologic complications. Analysis was performed using mixed graphical models, a machine learning approach that allows inference of cause-effect associations from continuous and discrete data. DESIGN Secondary analysis of a previous prospective observational study. SETTING PICU, single quaternary-care center. PATIENTS Individuals admitted to the PICU, younger than18 years old, with intravascular access via an indwelling catheter. INTERVENTIONS None. MEASUREMENTS About 101 patients were included in this analysis. Serum (days 1-7) was analyzed for glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, and alpha-II spectrin breakdown product 150 utilizing enzyme-linked immunosorbent assays. Serum levels of neuron-specific enolase, myelin basic protein, and S100 calcium binding protein B used in these models were reported previously. Demographic data, use of selected clinical therapies, lengths of stay, and ancillary neurologic testing (head CT, brain MRI, and electroencephalogram) results were recorded. The Mixed Graphical Model-Fast-Causal Inference-Maximum algorithm was applied to the dataset. MAIN RESULTS About 13 of 101 patients developed a neurologic complication during their critical illness. The mixed graphical model identified peak levels of the neuronal biomarker neuron-specific enolase and ubiquitin C-terminal hydrolase-L1, and the astrocyte biomarker glial fibrillary acidic protein to be the direct causal determinants for the development of a neurologic complication; in contrast, clinical variables including age, sex, length of stay, and primary neurologic diagnosis were not direct causal determinants. CONCLUSIONS Graphical models that include biomarkers in addition to clinical data are promising methods to evaluate direct relationships in the development of neurologic complications in critically ill children. Future work is required to validate and refine these models further, to determine if they can be used to predict which patients are at risk for/or with early neurologic complications.
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Affiliation(s)
- Vineet K. Raghu
- Department of Computer Science, University of Pittsburgh,
Pittsburgh, PA
| | - Christopher M. Horvat
- Department of Critical Care Medicine, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Department of Pediatrics, University
of Pittsburgh School of Medicine, Pittsburgh, PA
- Safar Center for Resuscitation Research, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Brain Care Institute, UPMC
Children’s Hospital of Pittsburgh, PA
| | - Patrick M. Kochanek
- Department of Critical Care Medicine, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Department of Pediatrics, University
of Pittsburgh School of Medicine, Pittsburgh, PA
- Safar Center for Resuscitation Research, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Brain Care Institute, UPMC
Children’s Hospital of Pittsburgh, PA
| | - Ericka L. Fink
- Department of Critical Care Medicine, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Department of Pediatrics, University
of Pittsburgh School of Medicine, Pittsburgh, PA
- Safar Center for Resuscitation Research, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Brain Care Institute, UPMC
Children’s Hospital of Pittsburgh, PA
| | - Robert S. B. Clark
- Department of Critical Care Medicine, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Department of Pediatrics, University
of Pittsburgh School of Medicine, Pittsburgh, PA
- Safar Center for Resuscitation Research, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Brain Care Institute, UPMC
Children’s Hospital of Pittsburgh, PA
| | - Panayiotis V. Benos
- Department of Computer Science, University of Pittsburgh,
Pittsburgh, PA
- Department of Computational and Systems Biology, University
of Pittsburgh, Pittsburgh PA
| | - Alicia K. Au
- Department of Critical Care Medicine, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Department of Pediatrics, University
of Pittsburgh School of Medicine, Pittsburgh, PA
- Safar Center for Resuscitation Research, University of
Pittsburgh School of Medicine, Pittsburgh, PA; Brain Care Institute, UPMC
Children’s Hospital of Pittsburgh, PA
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49
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Edalatfar M, Piri SM, Mehrabinejad MM, Mousavi MS, Meknatkhah S, Fattahi MR, Kavyani Z, Hajighadery A, Kaveh M, Aryannejad A, Ghafouri M, Jamshidi E, Rezwanifar MM, Sadeghi-Naini M, Bari A, Sharif-Alhoseini M. Biofluid Biomarkers in Traumatic Brain Injury: A Systematic Scoping Review. Neurocrit Care 2021; 35:559-572. [PMID: 33403583 DOI: 10.1007/s12028-020-01173-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 12/01/2020] [Indexed: 02/05/2023]
Abstract
Emerging evidence suggests that biofluid-based biomarkers have diagnostic and prognostic potential in traumatic brain injuries (TBI). However, owing to the lack of a conceptual framework or comprehensive review, it is difficult to visualize the breadth of materials that might be available. We conducted a systematic scoping review to map and categorize the evidence regarding biofluid-based biochemical markers of TBI. A comprehensive search was undertaken in January 2019. Of 25,354 records identified through the literature search, 1036 original human studies were included. Five hundred forty biofluid biomarkers were extracted from included studies and classified into 19 distinct categories. Three categories of biomarkers including cytokines, coagulation tests, and nerve tissue proteins were investigated more than others and assessed in almost half of the studies (560, 515, and 502 from 1036 studies, respectively). S100 beta as the most common biomarker for TBI was tested in 21.2% of studies (220 articles). Cortisol was the only biomarker measured in blood, cerebrospinal fluid, urine, and saliva. The most common sampling time was at admission and within 24 h of injury. The included studies focused mainly on biomarkers from blood and central nervous system sources, the adult population, and severe and blunt injuries. The most common outcome measures used in studies were changes in biomarker concentration level, Glasgow coma scale, Glasgow outcome scale, brain computed tomography scan, and mortality rate. Biofluid biomarkers could be clinically helpful in the diagnosis and prognosis of TBI. However, there was no single definitive biomarker with accurate characteristics. The present categorization would be a road map to investigate the biomarkers of the brain injury cascade separately and detect the most representative biomarker of each category. Also, this comprehensive categorization could provide a guiding framework to design combined panels of multiple biomarkers.
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Affiliation(s)
- Maryam Edalatfar
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
| | - Seyed Mohammad Piri
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
| | - Mohammad-Mehdi Mehrabinejad
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
- Department of Radiology, Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran
| | - Monireh-Sadat Mousavi
- Laboratory of Neuro-Organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Sogol Meknatkhah
- Laboratory of Neuro-Organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Mohammad-Reza Fattahi
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
- Department of Sports and Exercise Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Kavyani
- Maternal-Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdolkarim Hajighadery
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
| | - Meysam Kaveh
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
| | - Armin Aryannejad
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
| | - Mohammad Ghafouri
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
| | - Elham Jamshidi
- Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohamad Mehdi Rezwanifar
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran
| | - Mohsen Sadeghi-Naini
- Department of Neurosurgery, Imam Hossein Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Ausaf Bari
- Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Mahdi Sharif-Alhoseini
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Sina Hospital, Hassan-Abad Square, Imam Khomeini Ave, Tehran, 11365-3876, Iran.
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50
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Kurakina АS, Semenova TN, Guzanova EV, Nesterova VN, Schelchkova NA, Mukhina IV, Grigoryeva VN. Prognostic Value of Investigating Neuron-Specific Enolase in Patients with Ischemic Stroke. Sovrem Tekhnologii Med 2021; 13:68-72. [PMID: 34513079 PMCID: PMC8353723 DOI: 10.17691/stm2021.13.2.08] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Indexed: 11/24/2022] Open
Abstract
The aim of the study was to assess the prognostic value of the plasma neuron-specific enolase (NSE) level as a predictor of functional outcome and motor function recovery in the acute period of ischemic stroke (IS).
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Affiliation(s)
- А S Kurakina
- Assistant, Department of Neurology and Medical Genetics, Perm State Medical University named after Academician E.A. Wagner, 26 Petropavlovskaya St., Perm, 614990, Russia
| | - T N Semenova
- Assistant, Department of Neurological Diseases, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - E V Guzanova
- Associate Professor, Department of Neurological Diseases, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - V N Nesterova
- Chief of Regional Vascular Center No.23; Head of the Unit for Patients with Acute Disorder of Cerebral Circulation, Nizhny Novgorod Regional Clinical Hospital named after N.A. Semashko, 190 Rodionova St., Nizhny Novgorod, 603126, Russia
| | - N A Schelchkova
- Head of the Central Scientific Research Laboratory, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Associate Professor, Department of Normal Physiology named after N.Y. Belenkov, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - I V Mukhina
- Professor, Director of the Institute of Fundamental Medicine, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Head of the Department of Normal Physiology named after N.Y. Belenkov, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - V N Grigoryeva
- Professor, Head of the Department of Neurological Diseases, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
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