Co-Expression Network Analysis of MicroRNAs and Proteins in Severe Traumatic Brain Injury: A Systematic Review

Traumatic brain injury (TBI) represents one of the leading causes of mortality and morbidity worldwide, placing an enormous socioeconomic burden on healthcare services and communities around the world. Survivors of TBI can experience complications ranging from temporary neurological and psychosocial problems to long-term, severe disability and neurodegenerative disease. The current lack of therapeutic agents able to mitigate the effects of secondary brain injury highlights the urgent need for novel target discovery. This study comprises two independent systematic reviews, investigating both microRNA (miRNA) and proteomic expression in rat models of severe TBI (sTBI). The results were combined to perform integrated miRNA-protein co-expression analyses with the aim of uncovering the potential roles of miRNAs in sTBI and to ultimately identify new targets for therapy. Thirty-four studies were included in total. Bioinformatic analysis was performed to identify any miRNA–protein associations. Endocytosis and TNF signalling pathways were highlighted as common pathways involving both miRNAs and proteins found to be differentially expressed in rat brain tissue following sTBI, suggesting efforts to find novel therapeutic targets that should be focused here. Further high-quality investigations are required to ascertain the involvement of these pathways and their miRNAs in the pathogenesis of TBI and other CNS diseases and to therefore uncover those targets with the greatest therapeutic potential.

Download Full-text

Fine Tuning of Traumatic Brain Injury Management in Neurointensive Care—Indicative Observations and Future Perspectives

Frontiers in Neurology ◽

10.3389/fneur.2021.638132 ◽

2021 ◽

Vol 12 ◽

Author(s):

Teodor M. Svedung Wettervik ◽

Anders Lewén ◽

Per Enblad

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Fine Tuning ◽

Neurointensive Care ◽

Secondary Brain Injury ◽

Brain Tissue Oxygenation ◽

Treatment Protocols ◽

Injury Mechanisms ◽

Severe Tbi ◽

Type Of Injury

Neurointensive care (NIC) has contributed to great improvements in clinical outcomes for patients with severe traumatic brain injury (TBI) by preventing, detecting, and treating secondary insults and thereby reducing secondary brain injury. Traditional NIC management has mainly focused on generally applicable escalated treatment protocols to avoid high intracranial pressure (ICP) and to keep the cerebral perfusion pressure (CPP) at sufficiently high levels. However, TBI is a very heterogeneous disease regarding the type of injury, age, comorbidity, secondary injury mechanisms, etc. In recent years, the introduction of multimodality monitoring, including, e.g., pressure autoregulation, brain tissue oxygenation, and cerebral energy metabolism, in addition to ICP and CPP, has increased the understanding of the complex pathophysiology and the physiological effects of treatments in this condition. In this article, we will present some potential future approaches for more individualized patient management and fine-tuning of NIC, taking advantage of multimodal monitoring to further improve outcome after severe TBI.

Download Full-text

HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model

Cellular Physiology and Biochemistry ◽

10.1159/000489659 ◽

2018 ◽

Vol 46 (6) ◽

pp. 2532-2542 ◽

Cited By ~ 15

Author(s):

Lijun Yang ◽

Feng Wang ◽

Liang Yang ◽

Yunchao Yuan ◽

Yan Chen ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Edema ◽

Therapeutic Potential ◽

High Mobility ◽

Neurological Injury ◽

Secondary Brain Injury ◽

Cell Degeneration ◽

Injured Brain ◽

Walking Tests

Background/Aims: Traumatic brain injury (TBI) is a complex neurological injury in young adults lacking effective treatment. Emerging evidences suggest that inflammation contributes to the secondary brain injury following TBI, including breakdown of the blood brain barrier (BBB), subsequent edema and neurological deterioration. High mobility group box-1 (HMGB1) has been identified as a key cytokine in the inflammation reaction following TBI. Here, we investigated the therapeutic efficacy of HMGB1 A-box fragment, an antagonist competing with full-length HMGB1 for receptor binding, against TBI. Methods: TBI was induced by controlled cortical impact (CCI) in adult male mice. HMGB1 A-box fragment was given intravenously at 2 mg/kg/day for 3 days after CCI. HMGB1 A-box-treated CCI mice were compared with saline-treated CCI mice and sham mice in terms of BBB disruption evaluated by Evan’s blue extravasation, brain edema by brain water content, cell death by propidium iodide staining, inflammation by Western blot and ELISA assay for cytokine productions, as well as neurological functions by the modified Neurological Severity Score, wire grip and beam walking tests. Results: HMGB1 A-box reversed brain damages in the mice following TBI. It significantly reduced brain edema by protecting integrity of the BBB, ameliorated cell degeneration, and decreased expression of pro-inflammatory cytokines released in injured brain after TBI. These cellular and molecular effects were accompanied by improved behavioral performance in TBI mice. Notably, HMGB1 A-box blocked IL-1β-induced HMGB1 release, and preferentially attenuated TLR4, Myd88 and P65 in astrocyte cultures. Conclusion: Our data suggest that HMGB1 is involved in CCI-induced TBI, which can be inhibited by HMGB1 A-box fragment. Therefore, HMGB1 A-box fragment may have therapeutic potential for the secondary brain damages in TBI.

Download Full-text

Predictors of recovery in moderate to severe traumatic brain injury

Journal of Neurosurgery ◽

10.3171/2018.4.jns172185 ◽

2019 ◽

Vol 131 (5) ◽

pp. 1648-1657

Author(s):

Kadhaya David Muballe ◽

Constance R. Sewani-Rusike ◽

Benjamin Longo-Mbenza ◽

Jehu Iputo

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Glasgow Coma Scale ◽

Clinical Outcomes ◽

Secondary Brain Injury ◽

Coma Scale ◽

Severity Of Injury ◽

Severe Tbi

OBJECTIVETraumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Clinical outcomes in TBI are determined by the severity of injury, which is dependent on the primary and secondary brain injury processes. Whereas primary brain injury lesions are related to the site of impact, secondary brain injury results from physiological changes caused by oxidative stress and inflammatory responses that occur after the primary insult. The aim of this study was to identify important clinical and biomarker profiles that were predictive of recovery after moderate to severe TBI. A good functional outcome was defined as a Glasgow Outcome Scale (GOS) score of ≥ 4.METHODSThis was a prospective study of patients with moderate to severe TBI managed at the Nelson Mandela Academic Hospital during the period between March 2014 and March 2016. Following admission and initial management, the patient demographic data (sex, age) and admission Glasgow Coma Scale score were recorded. Oxidative stress and inflammatory biomarkers in blood and CSF were sampled on days 1–7. On day 14, only blood was sampled for the same biomarkers. The primary outcome was the GOS score—due to its simplicity, the GOS was used to assess clinical outcomes at day 90. Because of difficulty in performing regular follow-up due to the vastness of the region, difficult terrain, and long travel distances, a 3-month follow-up period was used to avoid default.RESULTSSixty-four patients with Glasgow Coma Scale scores of ≤ 12 were seen and managed. Among the 56 patients who survived, 42 showed significant recovery (GOS score ≥ 4) at 3 months. Important predictors of recovery included antioxidant activity in the CSF (superoxide dismutase and total antioxidant capacity).CONCLUSIONSRecovery after TBI was dependent on the resolution of oxidative stress imbalance.

Download Full-text

Integrative Neuroinformatics for Precision Prognostication and Personalized Therapeutics in Moderate and Severe Traumatic Brain Injury

Frontiers in Neurology ◽

10.3389/fneur.2021.729184 ◽

2021 ◽

Vol 12 ◽

Author(s):

Frederick A. Zeiler ◽

Yasser Iturria-Medina ◽

Eric P. Thelin ◽

Alwyn Gomez ◽

Jai J. Shankar ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Severe Traumatic Brain Injury ◽

Management Strategies ◽

Current Status ◽

Data Sets ◽

Omics Data ◽

Mortality And Morbidity ◽

Daunting Task ◽

Severe Tbi

Despite changes in guideline-based management of moderate/severe traumatic brain injury (TBI) over the preceding decades, little impact on mortality and morbidity have been seen. This argues against the “one-treatment fits all” approach to such management strategies. With this, some preliminary advances in the area of personalized medicine in TBI care have displayed promising results. However, to continue transitioning toward individually-tailored care, we require integration of complex “-omics” data sets. The past few decades have seen dramatic increases in the volume of complex multi-modal data in moderate and severe TBI care. Such data includes serial high-fidelity multi-modal characterization of the cerebral physiome, serum/cerebrospinal fluid proteomics, admission genetic profiles, and serial advanced neuroimaging modalities. Integrating these complex and serially obtained data sets, with patient baseline demographics, treatment information and clinical outcomes over time, can be a daunting task for the treating clinician. Within this review, we highlight the current status of such multi-modal omics data sets in moderate/severe TBI, current limitations to the utilization of such data, and a potential path forward through employing integrative neuroinformatic approaches, which are applied in other neuropathologies. Such advances are positioned to facilitate the transition to precision prognostication and inform a top-down approach to the development of personalized therapeutics in moderate/severe TBI.

Download Full-text

History, Overview, and Human Anatomical Pathology of Traumatic Brain Injury

Neurotrauma ◽

10.1093/med/9780190279431.003.0001 ◽

2018 ◽

pp. 3-12

Author(s):

Kentaro Shimoda ◽

Shoji Yokobori ◽

Ross Bullock

Keyword(s):

Traumatic Brain Injury ◽

Young Adults ◽

Intensive Care ◽

Brain Injury ◽

Brain Injuries ◽

Research Effort ◽

Intensive Care Treatment ◽

Mortality And Morbidity ◽

Severe Tbi ◽

Anatomical Pathology

Traumatic brain injury (TBI) is one of the oldest and commonest causes of medical distress in humans. However, despite much research effort, the prognosis for severe TBI patients remains poor. Worldwide, TBI is recognized as the leading cause of mortality and morbidity in young adults. TBI is a major worldwide health and socioeconomic problem. The most important factor in the prognosis of TBI patients is the severity of the "primary" brain injury. Additional delayed "secondary" brain damage continues from the time of traumatic impact in TBI patients, and the two combine to determine outcome. This chapter discusses the incidence of TBI, trends in morbidity and mortality, shifts in causes of TBI, its economic burden on society, and the pathophysiology of primary and secondary brain injuries. The authors discuss indications for surgical and intensive care treatment for intracranial hypertension and mass lesion management in TBI patients.

Download Full-text

Biologic Effect of Hydrogen Sulfide and Its Role in Traumatic Brain Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7301615 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Jiaxin Zhang ◽

Shaoyi Zhang ◽

Haiyan Shan ◽

Mingyang Zhang

Keyword(s):

Traumatic Brain Injury ◽

Hydrogen Sulfide ◽

Brain Injury ◽

Therapeutic Potential ◽

Long Term Potentiation ◽

Secondary Brain Injury ◽

Term Potentiation ◽

Great Hope ◽

Biologic Effects ◽

Physiological Dose

Ever since endogenous hydrogen sulfide (H2S) was found in mammals in 1989, accumulated evidence has demonstrated that H2S functions as a novel neurological gasotransmitter in brain tissues and may play a key role in traumatic brain injury. It has been proved that H2S has an antioxidant, anti-inflammatory, and antiapoptosis function in the neuron system and functions as a neuroprotective factor against secondary brain injury. In addition, H2S has other biologic effects such as regulating the intracellular concentration of Ca2+, facilitating hippocampal long-term potentiation (LTP), and activating ATP-sensitive K channels. Due to the toxic nature of H2S when exceeding the physiological dose in the human body, only a small amount of H2S-related therapies was applied to clinical treatment. Therefore, it has huge therapeutic potential and has great hope for recovering patients with traumatic brain injury.

Download Full-text

Management and Challenges of Severe Traumatic Brain Injury

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0040-1716493 ◽

2020 ◽

Author(s):

Shayan Rakhit ◽

Mina F. Nordness ◽

Sarah R. Lombardo ◽

Madison Cook ◽

Laney Smith ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Great Promise ◽

Secondary Brain Injury ◽

Trauma Patients ◽

Barbiturate Coma ◽

High Quality Research ◽

Paroxysmal Sympathetic Hyperactivity ◽

Vte Prophylaxis ◽

Severe Tbi

AbstractTraumatic brain injury (TBI) is the leading cause of death and disability in trauma patients, and can be classified into mild, moderate, and severe by the Glasgow coma scale (GCS). Prehospital, initial emergency department, and subsequent intensive care unit (ICU) management of severe TBI should focus on avoiding secondary brain injury from hypotension and hypoxia, with appropriate reversal of anticoagulation and surgical evacuation of mass lesions as indicated. Utilizing principles based on the Monro–Kellie doctrine and cerebral perfusion pressure (CPP), a surrogate for cerebral blood flow (CBF) should be maintained by optimizing mean arterial pressure (MAP), through fluids and vasopressors, and/or decreasing intracranial pressure (ICP), through bedside maneuvers, sedation, hyperosmolar therapy, cerebrospinal fluid (CSF) drainage, and, in refractory cases, barbiturate coma or decompressive craniectomy (DC). While controversial, direct ICP monitoring, in conjunction with clinical examination and imaging as indicated, should help guide severe TBI therapy, although new modalities, such as brain tissue oxygen (PbtO2) monitoring, show great promise in providing strategies to optimize CBF. Optimization of the acute care of severe TBI should include recognition and treatment of paroxysmal sympathetic hyperactivity (PSH), early seizure prophylaxis, venous thromboembolism (VTE) prophylaxis, and nutrition optimization. Despite this, severe TBI remains a devastating injury and palliative care principles should be applied early. To better affect the challenging long-term outcomes of severe TBI, more and continued high quality research is required.

Download Full-text

Microstructural Basis of Contusion Expansion in Traumatic Brain Injury: Insights from Diffusion Tensor Imaging

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.11 ◽

2013 ◽

Vol 33 (6) ◽

pp. 855-862 ◽

Cited By ~ 37

Author(s):

Virginia FJ Newcombe ◽

Guy B Williams ◽

Joanne G Outtrim ◽

Doris Chatfield ◽

M Gulia Abate ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Diffusion Tensor Imaging ◽

Brain Injury ◽

Diffusion Tensor ◽

Secondary Brain Injury ◽

Mortality And Morbidity ◽

Apparent Diffusion ◽

Causes Of Mortality ◽

Initial Imaging ◽

Injury Progression

Traumatic brain injury (TBI) is often exacerbated by events that lead to secondary brain injury, and represent potentially modifiable causes of mortality and morbidity. Diffusion tensor imaging was used to characterize tissue at-risk in a group of 35 patients scanned at a median of 50 hours after injury. Injury progression was assessed in a subset of 16 patients with two scans. All contusions within the first few days of injury showed a core of restricted diffusion, surrounded by an area of raised apparent diffusion coefficient (ADC). In addition to these two well-defined regions, a thinner rim of reduced ADC was observed surrounding the region of increased ADC in 91% of patients scanned within the first 3 days after injury. In patients who underwent serial imaging, the rim of ADC hypointensity was subsumed into the high ADC region as the contusion enlarged. Overall contusion enlargement tended to be more frequent with early lesions, but its extent was unrelated to the time of initial imaging, initial contusion size, or the presence of hemostatic abnormalities. This rim of hypointensity may characterize a region of microvascular failure resulting in cytotoxic edema, and may represent a ‘traumatic penumbra’ which may be rescued by effective therapy.

Download Full-text

Usability of the Level of the S100B Protein, the Gosling Pulsatility Index, and the Jugular Venous Oxygen Saturation for the Prediction of Mortality and Morbidity in Patients with Severe Traumatic Brain Injury

BioMed Research International ◽

10.1155/2021/2398488 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Ryszard Tomasiuk ◽

Sebastian Dzierzęcki ◽

Artur Zaczyński ◽

Mirosław Ząbek

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Oxygen Saturation ◽

Pulsatility Index ◽

Economic Stress ◽

S100b Protein ◽

Mortality And Morbidity ◽

Serum S100b ◽

Prediction Of Mortality ◽

Severe Tbi

The high frequency of traumatic brain injury imposes severe economic stress on health and insurance services. The objective of this study was to analyze the association between the serum S100B protein, the Gosling pulsatility index (PI), and the level of oxygen saturation at the tip of the internal jugular vein (SjVO2%) in patients diagnosed with severe TBI. The severity of TBI was assessed by a GCS score ≤ 8 stratified by Glasgow outcome scale (GOS) measured on the day of discharge from the hospital. Two groups were included: GOS < 4 (unfavorable group (UG)) and GOS ≥ 4 (favorable group (UG)). S100B levels were higher in the UG than in the FG. PI levels in the UG were also substantially higher than in the FG. There were similar levels of SjVO2 in the two groups. This study confirmed that serum S100B levels were higher in patients with unfavorable outcomes than in those with favorable outcomes. Moreover, a clear demarcation in PI between unfavorable and FGs was observed. This report shows that mortality and morbidity rates in patients with traumatic brain injury can be assessed within the first 4 days of hospitalization using the S100B protein, PI values, and SjVO2.

Download Full-text

Decision-making for decompressive craniectomy in traumatic brain injury aided by multimodality monitoring: illustrative case

Journal of Neurosurgery: Case Lessons ◽

10.3171/case2197 ◽

2021 ◽

Vol 1 (25) ◽

Author(s):

Myranda B. Robinson ◽

Peter Shin ◽

Robert Alunday ◽

Chad Cole ◽

Michel T. Torbey ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Decision Making ◽

Brain Injury ◽

Decompressive Craniectomy ◽

Pupillary Response ◽

Illustrative Case ◽

Secondary Brain Injury ◽

Brain Tissue Oxygenation ◽

Multimodality Monitoring ◽

Severe Tbi

BACKGROUND Severe traumatic brain injury (TBI) requires individualized, physiology-based management to avoid secondary brain injury. Recent improvements in quantitative assessments of metabolism, oxygenation, and subtle examination changes may potentially allow for more targeted, rational approaches beyond simple intracranial pressure (ICP)-based management. The authors present a case in which multimodality monitoring assisted in decision-making for decompressive craniectomy. OBSERVATIONS This patient sustained a severe TBI without mass lesion and was monitored with a multimodality approach. Although imaging did not seem grossly worrisome, ICP, pressure reactivity, brain tissue oxygenation, and pupillary response all began worsening, pushing toward decompressive craniectomy. All parameters normalized after decompression, and the patient had a satisfactory clinical outcome. LESSONS Given recent conflicting randomized trials on the utility of decompressive craniectomy in severe TBI, precision, physiology-based approaches may offer an improved strategy to determine who is most likely to benefit from aggressive treatment. Trials are underway to test components of these strategies.

Download Full-text