Cellular Senescence in Traumatic Brain Injury: Evidence and Perspectives

Mild traumatic brain injury (mTBI) can lead to long-term neurological dysfunction and increase one's risk of neurodegenerative disease. Several repercussions of mTBI have been identified and well-studied, including neuroinflammation, gliosis, microgliosis, excitotoxicity, and proteinopathy – however the pathophysiological mechanisms activating these pathways after mTBI remains controversial and unclear. Emerging research suggests DNA damage-induced cellular senescence as a possible driver of mTBI-related sequalae. Cellular senescence is a state of chronic cell-cycle arrest and inflammation associated with physiological aging, mood disorders, dementia, and various neurodegenerative pathologies. This narrative review evaluates the existing studies which identify DNA damage or cellular senescence after TBI (including mild, moderate, and severe TBI) in both experimental animal models and human studies, and outlines how cellular senescence may functionally explain both the molecular and clinical manifestations of TBI. Studies on this subject clearly show accumulation of various forms of DNA damage (including oxidative damage, single-strand breaks, and double-strand breaks) and senescent cells after TBI, and indicate that cellular senescence may be an early event after TBI. Further studies are required to understand the role of sex, cell-type specific mechanisms, and temporal patterns, as senescence may be a pathway of interest to target for therapeutic purposes including prognosis and treatment.

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Early onset senescence and cognitive impairment in a murine model of repeated mTBI

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01190-x ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Nicole Schwab ◽

YoungJun Ju ◽

Lili-Naz Hazrati

Keyword(s):

Gene Expression ◽

Traumatic Brain Injury ◽

Dna Damage ◽

Cognitive Impairment ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Cellular Senescence ◽

Early Gene ◽

Dna Breaks ◽

Post Injury

AbstractMild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell–cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.

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ESPECIALLY CELLULAR IMMUNITY IN PATIENTS WITH TRAUMATIC BRAIN INJURY OF DIFFERENT SEVERITY IN ACUTE PERIOD

Medical academic journal ◽

10.17816/maj191s196-98 ◽

2019 ◽

Vol 19 (1S) ◽

pp. 96-98

Author(s):

A O Norka ◽

R N Kuznetsova ◽

S V Kudryavtsev ◽

S N Kovalenko ◽

M K Serebriakova ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Immune System ◽

Brain Injury ◽

Th17 Cells ◽

Clinical Manifestations ◽

Th2 Cells ◽

Cd4 Cells ◽

Acute Period ◽

Healthy Donors ◽

Severe Tbi

Currently, it is known that in response to brain damage a reaction from the immune system is triggered, but its role in the formation of clinical manifestations remains a little-studied problem to date. Using multicolor cytometric analysis, a study was conducted to determine the number of Th1-, Th2-, Tfh- and Th17-cells among CD45RA-negative CD3+CD4+ cells in a group of patients with mild TBI (M-TBI, n = 20) and with moderate to severe TBI (MS-TBI, n = 16) and a group of conditionally healthy donors (n = 30). The imbalance between Th2 cells and Th17 cells was found in patients with TBI in the acute period, which probably predetermines the course of the disease and the development of complications.

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Traumatic brain injury: Future application of nanomedicine

GSC Advanced Research and Reviews ◽

10.30574/gscarr.2021.6.2.0019 ◽

2021 ◽

Vol 6 (2) ◽

pp. 020-027

Author(s):

Nasima Khanam ◽

Debjani Nath

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neurological Dysfunction ◽

Future Application ◽

Mild Tbi ◽

Severe Tbi ◽

Sports Arena ◽

The Military ◽

The Brain ◽

Brain Homeostasis

Traumatic brain injury (TBI) is currently a rising player in the cause of disability and neurological dysfunction worldwide. TBI is a common occurrence in the military and extreme activities, sports arena and accidents. Severe TBI can be fatal but mild TBI persists and progressively deteriorates brain homeostasis and physiology. Apart from the physical disabilities, psychological complexities arise in people with mild TBI. Despite the seriousness of this hazard, treatments for TBI are not adequate, mostly due to the brain being involved. Nanoparticle (NP) therapy seems to be an effective alternative to combat TBI. This review outlines the state of TBI and describes the probable medical support that nanomedicine can provide.

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Challenges and Opportunities for Neuroimaging in Young Patients with Traumatic Brain Injury: a Coordinated Effort towards Advancing Discovery from the ENIGMA Pediatric Moderate/Severe TBI Group

10.31234/osf.io/y2txh ◽

2019 ◽

Cited By ~ 4

Author(s):

Emily L. Dennis ◽

Karen Caeyenberghs ◽

Robert F. Asarnow ◽

Talin Babikian ◽

Brenda Bartnik-Olson ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Meta Analysis ◽

Young Patients ◽

Future Research ◽

Childhood And Adolescence ◽

Developmental Issues ◽

Challenges And Opportunities ◽

Severe Tbi ◽

Advance Research

Traumatic brain injury (TBI) is a major cause of death and disability in children in both developed and developing nations. Children and adolescents suffer from TBI at a higher rate than the general population; however, research in this population lags behind research in adults. This may be due, in part, to the smaller number of investigators engaged in research with this population and may also be related to changes in safety laws and clinical practice that have altered length of hospital stays, treatment, and access to this population. Specific developmental issues also warrant attention in studies of children, and the ever-changing context of childhood and adolescence may require larger sample sizes than are commonly available to adequately address remaining questions related to TBI. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric Moderate-Severe TBI (msTBI) group aims to advance research in this area through global collaborative meta-analysis. In this paper we discuss important challenges in pediatric TBI research and opportunities that we believe the ENIGMA Pediatric msTBI group can provide to address them. We conclude with recommendations for future research in this field of study.

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Modulated Neuroprotection in Unresponsive Wakefulness Syndrome after Severe Traumatic Brain Injury

Brain Sciences ◽

10.3390/brainsci11081044 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1044

Author(s):

Cristina Daia ◽

Cristian Scheau ◽

Aura Spinu ◽

Ioana Andone ◽

Cristina Popescu ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Glasgow Coma Scale ◽

Severe Traumatic Brain Injury ◽

Functional Independence ◽

Unresponsive Wakefulness Syndrome ◽

Coma Scale ◽

Severe Tbi ◽

Neuroprotective Treatment ◽

Gcs Score

Background: We aimed to assess the effects of modulated neuroprotection with intermittent administration in patients with unresponsive wakefulness syndrome (UWS) after severe traumatic brain injury (TBI). Methods: Retrospective analysis of 60 patients divided into two groups, with and without neuroprotective treatment with Actovegin, Cerebrolysin, pyritinol, L-phosphothreonine, L-glutamine, hydroxocobalamin, alpha-lipoic acid, carotene, DL-α-tocopherol, ascorbic acid, thiamine, pyridoxine, cyanocobalamin, Q 10 coenzyme, and L-carnitine alongside standard treatment. Main outcome measures: Glasgow Coma Scale (GCS) after TBI, Extended Glasgow Coma Scale (GOS E), Disability Rankin Scale (DRS), Functional Independence Measurement (FIM), and Montreal Cognitive Assessment (MOCA), all assessed at 1, 3, 6, 12, and 24 months after TBI. Results: Patients receiving neuroprotective treatment recovered more rapidly from UWS than controls (p = 0.007) passing through a state of minimal consciousness and gradually progressing until the final evaluation (p = 0.000), towards a high cognitive level MOCA = 22 ± 6 points, upper moderate disability GOS-E = 6 ± 1, DRS = 6 ± 4, and an assisted gait, FIM =101 ± 25. The improvement in cognitive and physical functioning was strongly correlated with lower UWS duration (−0.8532) and higher GCS score (0.9803). Conclusion: Modulated long-term neuroprotection may be the therapeutic key for patients to overcome UWS after severe TBI.

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Self-awareness four years after severe traumatic brain injury: discordance between the patient’s and relative’s complaints. Results from the PariS-TBI study

Clinical Rehabilitation ◽

10.1177/0269215517734294 ◽

2017 ◽

Vol 32 (5) ◽

pp. 692-704 ◽

Cited By ~ 6

Author(s):

Camille Chesnel ◽

Claire Jourdan ◽

Eleonore Bayen ◽

Idir Ghout ◽

Emmanuelle Darnoux ◽

...

Keyword(s):

Quality Of Life ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Severe Traumatic Brain Injury ◽

Significant Relationship ◽

Injury Severity ◽

Chronic Phase ◽

Functional Independence ◽

Severe Tbi

Objective: To evaluate the patient’s awareness of his or her difficulties in the chronic phase of severe traumatic brain injury (TBI) and to determine the factors related to poor awareness. Design/Setting/Subjects: This study was part of a larger prospective inception cohort study of patients with severe TBI in the Parisian region (PariS-TBI study). Intervention/Main measures: Evaluation was carried out at four years and included the Brain Injury Complaint Questionnaire (BICoQ) completed by the patient and his or her relative as well as the evaluation of impairments, disability and quality of life. Results: A total of 90 patient-relative pairs were included. Lack of awareness was measured using the unawareness index that corresponded to the number of discordant results between the patient and relative in the direction of under evaluation of difficulties by the patient. The only significant relationship found with lack of awareness was the subjective burden perceived by the relative (Zarit Burden Inventory) ( r = 0.5; P < 0.00001). There was no significant relationship between lack of awareness and injury severity, pre-injury socio-demographic data, cognitive impairments, mood disorders, functional independence (Barthel index), global disability (Glasgow Outcome Scale), return to work at four years or quality of life (Quality Of Life after Brain Injury scale (QOLIBRI)). Conclusion: Lack of awareness four years post severe TBI was not related to the severity of the initial trauma, sociodemographic data, the severity of impairments, limitations of activity and participation, or the patient’s quality of life. However, poor awareness did significantly influence the weight of the burden perceived by the relative.

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Early diagnosis of mortality using admission CT perfusion in severe traumatic brain injury patients (ACT-TBI): protocol for a prospective cohort study

BMJ Open ◽

10.1136/bmjopen-2020-047305 ◽

2021 ◽

Vol 11 (6) ◽

pp. e047305

Author(s):

Susan Alcock ◽

Divjeet Batoo ◽

Sudharsana Rao Ande ◽

Rob Grierson ◽

Marco Essig ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Cohort Study ◽

Brain Injury ◽

Early Diagnosis ◽

Hospital Mortality ◽

Brain Death ◽

Severe Traumatic Brain Injury ◽

Health Research ◽

Ct Perfusion ◽

Severe Tbi

IntroductionSevere traumatic brain injury (TBI) is a catastrophic neurological condition with significant economic burden. Early in-hospital mortality (<48 hours) with severe TBI is estimated at 50%. Several clinical examinations exist to determine brain death; however, most are difficult to elicit in the acute setting in patients with severe TBI. Having a definitive assessment tool would help predict early in-hospital mortality in this population. CT perfusion (CTP) has shown promise diagnosing early in-hospital mortality in patients with severe TBI and other populations. The purpose of this study is to validate admission CTP features of brain death relative to the clinical examination outcome for characterizing early in-hospital mortality in patients with severe TBI.Methods and analysisThe Early Diagnosis of Mortality using Admission CT Perfusion in Severe Traumatic Brain Injury Patients study, is a prospective cohort study in patients with severe TBI funded by a grant from the Canadian Institute of Health Research. Adults aged 18 or older, with evidence of a severe TBI (Glasgow Coma Scale score ≤8 before initial resuscitation) and, on mechanical ventilation at the time of imaging are eligible. Patients will undergo CTP at the time of first imaging on their hospital admission. Admission CTP compares with the reference standard of an accepted bedside clinical assessment for brainstem function. Deferred consent will be used. The primary outcome is a binary outcome of mortality (dead) or survival (not dead) in the first 48 hours of admission. The planned sample size for achieving a sensitivity of 75% and a specificity of 95% with a CI of ±5% is 200 patients.Ethics and disseminationThis study has been approved by the University of Manitoba Health Research Ethics Board. The findings from our study will be disseminated through peer-reviewed journals and presentations at local rounds, national and international conferences. The public will be informed through forums at the end of the study.Trial registration numberNCT04318665

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Moderate and severe traumatic brain injury: effect of blood alcohol concentration on Glasgow Coma Scale score and relation to computed tomography findings

Journal of Neurosurgery ◽

10.3171/2014.9.jns14322 ◽

2015 ◽

Vol 122 (1) ◽

pp. 211-218 ◽

Cited By ~ 28

Author(s):

Nils Petter Rundhaug ◽

Kent Gøran Moen ◽

Toril Skandsen ◽

Kari Schirmer-Mikalsen ◽

Stine B. Lund ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Injury Severity ◽

Blood Alcohol Concentration ◽

Alcohol Concentration ◽

Dependent Manner ◽

Blood Alcohol ◽

Severe Tbi ◽

Gcs Score ◽

Dose Dependent

OBJECT The influence of alcohol is assumed to reduce consciousness in patients with traumatic brain injury (TBI), but research findings are divergent. The aim of this investigation was to study the effects of different levels of blood alcohol concentration (BAC) on the Glasgow Coma Scale (GCS) scores in patients with moderate and severe TBI and to relate the findings to brain injury severity based on the admission CT scan. METHODS In this cohort study, 265 patients (age range 16–70 years) who were admitted to St. Olavs University Hospital with moderate and severe TBI during a 7-year period were prospectively registered. Of these, 217 patients (82%) had measured BAC. Effects of 4 BAC groups on GCS score were examined with ordinal logistic regression analyses, and the GCS scores were inverted to give an OR > 1. The Rotterdam CT score based on admission CT scan was used to adjust for brain injury severity (best score 1 and worst score 6) by stratifying patients into 2 brain injury severity groups (Rotterdam CT scores of 1–3 and 4–6). RESULTS Of all patients with measured BAC, 91% had intracranial CT findings and 43% had BAC > 0 mg/dl. The median GCS score was lower in the alcohol-positive patients (6.5, interquartile range [IQR] 4–10) than in the alcohol-negative patients (9, IQR 6–13; p < 0.01). No significant differences were found between alcohol-positive and alcohol-negative patients regarding other injury severity variables. Increasing BAC was a significant predictor of lower GCS score in a dose-dependent manner in age-adjusted analyses, with OR 2.7 (range 1.4–5.0) and 3.2 (range 1.5–6.9) for the 2 highest BAC groups (p < 0.01). Subgroup analyses showed an increasing effect of BAC group on GCS scores in patients with Rotterdam CT scores of 1–3: OR 3.1 (range 1.4–6.6) and 6.7 (range 2.7–16.7) for the 2 highest BAC groups (p < 0.01). No such relationship was found in patients with Rotterdam CT scores of 4–6 (p = 0.14–0.75). CONCLUSIONS Influence of alcohol significantly reduced the GCS score in a dose-dependent manner in patients with moderate and severe TBI and with Rotterdam CT scores of 1–3. In patients with Rotterdam CT scores of 4–6, and therefore more CT findings indicating increased intracranial pressure, the brain injury itself seemed to overrun the depressing effect of the alcohol on the CNS. This finding is in agreement with the assumption of many clinicians in the emergency situation.

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Abstract 230: Differential Effects of Prehospital Hypotension and Injury Severity in Isolated vs. Multisystem Major Traumatic Brain Injury

Circulation ◽

10.1161/circ.138.suppl_2.230 ◽

2018 ◽

Vol 138 (Suppl_2) ◽

Author(s):

Daniel W Spaite ◽

Chengcheng Hu ◽

Bentley J Bobrow ◽

Bruce J Barnhart ◽

Vatsal Chikani ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Injury Severity ◽

Treatment Effectiveness ◽

Guideline Implementation ◽

Body Region ◽

Head Region ◽

Differential Effects ◽

Severe Tbi

Background: In hospital-based studies, hypotension (HT, SBP <90) is more likely to occur in multisystem traumatic brain injury (MTBI) than isolated (ITBI). However, there are few EMS studies on this issue. Hypothesis: Prehospital HT is associated with differential effects in MTBI and ITBI and these effects are influenced by the severity of primary brain injury. Methods: Inclusion: TBI cases in the EPIC Study (NIH 1R01NS071049) before TBI guideline implementation (1/07-3/14). ITBI: Major TBI cases (CDC Barell Matrix Type 1) that had no injury with ICD9-based Regional Severity Score [RSS (AIS equivalent)] ≥3 in any other body region. MTBI: Type 1 TBI plus at least one non-head region injury with RSS ≥3. Results: Included were 13,435 cases [Excl: age <10 (5.9%), missing data (6.2%)]. 10,374 (77.2%) were ITBI, 3061 (22.8%) MTBI. Mortality: ITBI: 7.7% (797/10,374), MTBI: 19.2% (587/3061, p<0.0001). Prehospital HT occurred 3.5 times more often in MTBI (14.8%, 453/3061 vs 4.2%, 437/10,374; p<0.0001). Among HT cases, 40.8% (185/453) with MTBI died vs 30.9% with ITBI (135/437; p<0.0001). In the hypotensive moderate/severe TBI cohort (RSS-Head 3/4), MTBI mortality was 2.4 times higher (17.2%, 40/232) than ITBI (7.1%, 17/240, p = 0.001). However, in the hypotensive very/extremely severe TBI group (RSS-Head 5/6), mortality was almost identical in MTBI (73.4%, 141/192) and ITBI (72.1%, 116/161, p = 0.864). Conclusion: Among major TBI patients with prehospital HT, those with MTBI were much more likely to die than those with ITBI. However, this association varied dramatically with TBI severity. In mod/severe TBI cases with HT, MTBI mortality was 2.4 times higher than in ITBI. In contrast, in very/extremely severe TBI with HT, there was no identifiable mortality difference. Thus, in cases with substantial potential to survive the primary brain injury (mod/severe), outcome is markedly worse in patients with multisystem injuries. However, in very/extremely severe TBI, non-head region injuries have no apparent association with mortality. This may be because the TBI is the primary factor leading to death in these cases. The main EPIC study is evaluating whether this severity-based difference in “effect” has implications for TBI guideline treatment effectiveness.

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Glasgow outcome scale at hospital discharge as a prognostic index in patients with severe traumatic brain injury

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2012000800009 ◽

2012 ◽

Vol 70 (8) ◽

pp. 604-608 ◽

Cited By ~ 5

Author(s):

Rosmari A.R.A. Oliveira ◽

Sebastião Araújo ◽

Antonio L.E. Falcão ◽

Silvia M.T.P. Soares ◽

Carolina Kosour ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Medical Records ◽

Glasgow Outcome Scale ◽

Vegetative State ◽

Prognostic Index ◽

Prognostic Indicator ◽

Neurosurgical Procedures ◽

Severe Tbi ◽

Two Measures

OBJECTIVE: Evaluate the Glasgow outcome scale (GOS) at discharge (GOS-HD) as a prognostic indicator in patients with traumatic brain injury (TBI). METHOD: Retrospective data were collected of 45 patients, with Glasgow coma scale <8, age 25±10 years, 36 men, from medical records. Later, at home visit, two measures were scored: GOS-HD (according to information from family members) and GOS LATE (12 months after TBI). RESULTS: At discharge, the ERG showed: vegetative state (VS) in 2 (4%), severe disability (SD) in 27 (60%), moderate disability (MD) in 15 (33%) and good recovery (GR) in 1 (2%). After 12 months: death in 5 (11%), VS in 1 (2%), SD in 7 (16%), MD in 9 (20%) and GR in 23 (51%). Variables associated with poor outcome were: worse GOS-HD (p=0.03), neurosurgical procedures (p=0.008) and the kind of brain injury (p=0.009). CONCLUSION: The GOS-HD was indicator of prognosis in patients with severe TBI.

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