The Role of BDNF in Experimental and Clinical Traumatic Brain Injury.
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ABSTRACT:
SUBMITTER: Gustafsson D
PROVIDER: S-EPMC8037220 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neuronal plasticity is a fundamental factor in cognitive outcome following traumatic brain injury. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in this process. While there are many ways to measure cognitive outcome, general cognitive intelligence is a strong predictor of everyday decision-making, occupational attainment, social mobility and job performance. Thus it is an excellent measure of cognitive outcome following traumatic brain injury (TBI). Although the importance of the single-nucleotide polymorphisms polymorphism on cognitive function has been previously addressed, its role in recovery of general intelligence following TBI is unknown. We genotyped male Caucasian Vietnam combat veterans with focal penetrating TBI (pTBI) (n?=?109) and non-head injured controls (n?=?38) for 7 BDNF single-nucleotide polymorphisms. Subjects were administrated the Armed Forces Qualification Test (AFQT) at three different time periods: pre-injury on induction into the military, Phase II (10-15 years post-injury, and Phase III (30-35 years post-injury). Two single-nucleotide polymorphisms, rs7124442 and rs1519480, were significantly associated with post-injury recovery of general cognitive intelligence with the most pronounced effect at the Phase II time point, indicating lesion-induced plasticity. The genotypes accounted for 5% of the variance of the AFQT scores, independently of other significant predictors such as pre-injury intelligence and percentage of brain volume loss. These data indicate that genetic variations in BDNF play a significant role in lesion-induced recovery following pTBI. Identifying the underlying mechanism of this brain-derived neurotrophic factor effect could provide insight into an important aspect of post-traumatic cognitive recovery.
| S-EPMC3210804 | biostudies-literature
Project description:PURPOSE OF REVIEW:The underlying mechanisms responsible for chronic and progressive neurological damage after traumatic brain injury (TBI) are poorly understood, and therefore, current treatment options are limited. Proteomics is an emerging methodology to study changes to the TBI proteome in both patients and experimental models. RECENT FINDINGS:Although experimentally complex, mass spectrometry-based proteomics approaches are converging on a set of common methods. However, these methods are being applied to an increasingly diverse range of experimental models and types of injury. SUMMARY:In this review, our aim is to briefly describe experimental TBI models and the underlying methods common to most proteomic approaches. We will then review a series of articles that have recently appeared in which these approaches have been applied to important TBI questions. We will summarize several recent experimental studies, and suggest how the results of these emerging studies might impact future research as well as patient treatment.
| S-EPMC6221404 | biostudies-other
Project description:ObjectiveTo investigate possible electroencephalography (EEG) correlates of epileptogenesis after traumatic brain injury (TBI) using the fluid percussion model.MethodsExperiments were conducted on adult 2- to 4-month-old male Sprague-Dawley rats. Two groups of animals were studied: (1) the TBI group with depth and screw electrodes implanted immediately after the fluid percussion injury (FPI) procedure, and (2) a naive age-matched control group with the same electrode implantation montage. Pairs of tungsten microelectrodes (50 μm outer diameter) and screw electrodes were implanted in neocortex inside the TBI core, areas adjacent to TBI, and remote areas. EEG activity, recorded on the day of FPI, and continuously for 2 weeks, was analyzed for possible electrographic biomarkers of epileptogenesis. Video-EEG monitoring was also performed continuously in the TBI group to capture electrographic and behavioral seizures until the caps came off (28-189 days), and for 1 week, at 2, 3, and 6 months of age, in the control group.ResultsPathologic high-frequency oscillations (pHFOs) with a central frequency between 100 and 600 Hz, were recorded from microelectrodes, beginning during the first two post-FPI weeks, in 7 of 12 animals in the TBI group (58%) and never in the controls. pHFOs only occurred in cortical areas within or adjacent to the TBI core. These were associated with synchronous multiunit discharges and popSpikes, duration 15-40 msec. Repetitive pHFOs and EEG spikes (rHFOSs) formed paroxysmal activity, with a unique arcuate pattern, in the frequency band 10-16 Hz in the same areas as isolated pHFOs, and these events were also recorded by screw electrodes. Although loss of caps prevented long-term recordings from all rats, pHFOs and rHFOSs occurred during the first 2 weeks in all four animals that later developed seizures, and none of the rats without these events developed late seizures.SignificancepHFOs, similar to those associated with epileptogenesis in the status rat model of epilepsy, may also reflect epileptogenesis after FPI. rHFOSs could be noninvasive biomarkers of epileptogenesis.
| S-EPMC5081251 | biostudies-literature
Project description:Traumatic brain injury (TBI) is a worldwide medical problem, and currently, there are few therapeutic interventions that can protect the brain and improve functional outcomes in patients. Over the last several decades, experimental studies have investigated the pathophysiology of TBI and tested various pharmacological treatment interventions targeting specific mechanisms of secondary damage. Although many preclinical treatment studies have been encouraging, there remains a lack of successful translation to the clinic and no therapeutic treatments have shown benefit in phase 3 multicenter trials. Therapeutic hypothermia and targeted temperature management protocols over the last several decades have demonstrated successful reduction of secondary injury mechanisms and, in some selective cases, improved outcomes in specific TBI patient populations. However, the benefits of therapeutic hypothermia have not been demonstrated in multicenter randomized trials to significantly improve neurological outcomes. Although the exact reasons underlying the inability to translate therapeutic hypothermia into a larger clinical population are unknown, this failure may reflect the suboptimal use of this potentially powerful therapeutic in potentially treatable severe trauma patients. It is known that multiple factors including patient recruitment, clinical treatment variables, and cooling methodologies are all important in yielding beneficial effects. High-quality multicenter randomized controlled trials that incorporate these factors are required to maximize the benefits of this experimental therapy. This article therefore summarizes several factors that are important in enhancing the beneficial effects of therapeutic hypothermia in TBI. The current failures of hypothermic TBI clinical trials in terms of clinical protocol design, patient section, and other considerations are discussed and future directions are emphasized.
| S-EPMC6057704 | biostudies-other
Project description:The negative long-term effects of mild traumatic brain injury (mTBI) have been a growing concern in recent years, with accumulating evidence suggesting that mTBI combined with additional vulnerability factors may induce neurodegenerative-type changes in the brain. However, the factors instantiating risk for neurodegenerative disease following mTBI are unknown. This study examined the link between mTBI and brain-derived neurotrophic factor (BDNF) genotype, which has previously been shown to regulate processes involved in neurodegeneration including synaptic plasticity and facilitation of neural survival through its expression. Specifically, we examined nine BDNF single-nucleotide polymorphisms (SNPs; rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850, rs11030107, rs7127507 and rs12273363) previously associated with brain atrophy or memory deficits in mTBI. Participants were 165 white, non-Hispanic Iraq and Afghanistan war veterans between the ages of 19 and 58, 110 of whom had at least one mTBI in their lifetime. Results showed that the BDNF SNP rs1157659 interacted with mTBI to predict hippocampal volume. Furthermore, exploratory analysis of functional resting state data showed that rs1157659 minor allele homozygotes with a history of mTBI had reduced functional connectivity in the default mode network compared to major allele homozygotes and heterozygotes. Apolipoprotein E (APOE) was not a significant predictor of hippocampal volume or functional connectivity. These results suggest that rs1157659 minor allele homozygotes may be at greater risk for neurodegeneration after exposure to mTBI and provide further evidence for a potential role for BDNF in regulating neural processes following mTBI.
| S-EPMC5787402 | biostudies-literature
Project description:Worldwide elderly traumatic brain injury (TBI) patients tend to become an increasing burden to the society. Thus, a faster and less expensive way of evaluating TBI victims is needed. In the present study we investigated if optical coherence tomography (OCT) could be used as such a method. By using an animal model, we established if OCT can detect cortical changes in the acute phase of a penetrating TBI, in young (5-7 months) and old (20-22 months) rats. Due to the long-term evolution of TBI's, we wanted to investigate to what extent OCT could detect changes within the cortex in the chronic phase. Adult (7-12 months) male rats were used. Surprisingly, OCT imaging of the normal hemisphere was able to discriminate age-related differences in the mean gray values (MGV) of recorded pixels (p = .032). Furthermore, in the acute phase of TBI, OCT images recorded at 24 hr after the injury showed differences between the apparent damaged area of young and aged animals. Changes of MGV and skewness were only recorded 48 hr after injury. Monitoring the chronical evolution of the TBI with OCT revealed changes over time exceeding the normal range recorded for MGV, skewness and kurtosis, 14 and 21 days after TBI. Although in the present study we still used an extremely invasive approach, as technology improves, less invasive and non-harmful ways of recording OCT may allow for an objective way to detect changes within the brain structure after brain injuries.
| S-EPMC7891427 | biostudies-literature
Project description:Traumatic brain injury (TBI) is one of the leading causes of morbidity, disability and mortality across all age groups globally. Currently, only palliative treatments exist, but these are suboptimal and do little to combat the progressive damage to the brain that occurs after a TBI. However, multiple experimental treatments are currently available that target the primary and secondary biochemical and cellular changes that occur after a TBI. Some of these drugs have progressed to clinical trials and are currently being evaluated for their therapeutic benefits in TBI patients. The aim of this study was to identify which drugs are currently being evaluated in clinical trials for TBI. A search of ClinicalTrials.gov was performed on 3 December 2021 and all clinical trials that mentioned "TBI" OR "traumatic brain injury" AND "drug" were searched, revealing 362 registered trials. Of the trials, 46 were excluded due to the drug not being mentioned, leaving 138 that were completed and 116 that were withdrawn. Although the studies included 267,298 TBI patients, the average number of patients per study was 865 with a range of 5-200,000. Of the completed studies, 125 different drugs were tested in TBI patients but only 7 drugs were used in more than three studies, including amantadine, botulinum toxin A and tranexamic acid (TXA). However, previous clinical studies using these seven drugs showed variable results. The current study concludes that clinical trials in TBI have to be carefully conducted so as to reduce variability across studies, since the severity of TBI and timing of therapeutic interventions were key aspects of trial success.
| S-EPMC9138587 | biostudies-literature
Project description:BackgroundTraumatic brain injury (TBI) involves several aspects of a patient's condition, including physical, mental, emotional, cognitive, social, and functional changes. Therefore, a clinical trial with individuals with TBI should consider outcome measures that reflect their global status.MethodsWe present the work of the National Institute of Child Health and Development-sponsored Traumatic Brain Injury Clinical Trials Network Outcome Measures subcommittee and its choice of outcome measures for a phase III clinical trial of patients with complicated mild to severe TBI.ResultsOn the basis of theoretical and practical considerations, the subcommittee recommended the adoption of a core of 9 measures that cover 2 different areas of recovery: functional and cognitive. These measures are the Extended Glasgow Outcome Scale; the Controlled Oral Word Association Test; the Trail Making Test, Parts A and B; the California Verbal Learning Test-II; the Wechsler Adult Intelligence Scale-III Digit Span subtest; the Wechsler Adult Intelligence Scale-III Processing Speed Index; and the Stroop Color-Word Matching Test, Parts 1 and 2.ConclusionsThe statistical methods proposed to analyze these measures using a global test procedure, along with research and methodological and regulatory issues involved with the use of multiple outcomes in a clinical trial, are discussed.
| S-EPMC2939167 | biostudies-literature
Project description:BACKGROUND:Brain-derived neurotrophic factor (BDNF) is one of the most abundant neurotrophins in the adult brain, and it plays important roles in modulating synaptic plasticity and synaptogenesis. This study attempted to elucidate the role of the BDNF variant rs6265 in emotional symptoms following mild traumatic brain injury (mTBI). METHODS:To investigate the association between BDNF Val66Met polymorphism (rs6265) and emotional symptoms in mTBI patients, we recruited 192 mTBI patients and evaluated their Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scores in the first and sixth week after mTBI. RESULTS:The patients carrying the T allele of rs6265 had significantly higher BAI scores in the first week following mTBI. In addition, the patients carrying the T allele also showed higher scores of BDI in the first week. In the gender-specific subgroup analysis, the male patients carrying the T allele of rs6265 had higher scores of both BAI and BDI in the first and sixth week. Meanwhile, female patients carrying the T allele also had significantly higher scores of BDI in the first week following mTBI. CONCLUSIONS:This study provides evidence for the association between the BDNF variant rs6265 and emotional symptoms following mTBI.
| S-EPMC5776765 | biostudies-literature
Project description:IntroductionThere is no widely used method for communicating the possible need for surgical intervention in patients with traumatic brain injury (TBI). This study describes a scoring system designed to communicate the potential need for surgical decompression in TBI patients. The scoring system, named the Surgical Intervention for Traumatic Injury (SITI), was designed to be objective and easy to use.MethodsThe SITI scale uses radiographic and clinical findings, including the Glasgow Coma Scale Score, pupil examination, and findings noted on computed tomography. To examine the scale, we used the patient database for the Progesterone for the Treatment of Traumatic Brain Injury III (ProTECT III) trial, and retrospectively applied the SITI scale to these patients.ResultsOf the 871 patients reviewed, 164 (18.8%) underwent craniotomy or craniectomy, and 707 (81.2%) were treated nonoperatively. The mean SITI score was 5.1 for patients who underwent surgery and 2.5 for patients treated nonoperatively (P<0.001). The area under the receiver operating characteristic curve was 0.887.ConclusionThe SITI scale was designed to be a simple, objective, clinical decision tool regarding the potential need for surgical decompression after TBI. Application of the SITI scale to the ProTECT III database demonstrated that a score of 3 or more was well associated with a perceived need for surgical decompression. These results further demonstrate the potential utility of the SITI scale in clinical practice.
| S-EPMC6625684 | biostudies-literature