Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2?/? mice

Cerebral inflammation involves molecular cascades contributing to progressive damage after traumatic brain injury (TBI). The chemokine CC ligand-2 (CCL2) (formerly monocyte chemoattractant protein-1, MCP-1) is implicated in macrophage recruitment into damaged parenchyma after TBI. This study analyzed the presence of CCL2 in human TBI, and further investigated the role of CCL2 in physiological and cellular mechanisms of secondary brain damage after TBI. Sustained elevation of CCL2 was detected in the cerebrospinal fluid (CSF) of severe TBI patients for 10 days after trauma, and in cortical homogenates of C57Bl/6 mice, peaking at 4 to 12 h after closed head injury (CHI). Neurological outcome, lesion volume, macrophage/microglia infiltration, astrogliosis, and the cerebral cytokine network were thus examined in CCL2-deficient (−/−) mice subjected to CHI. We found that CCL2−/− mice showed altered production of multiple cytokines acutely (2 to 24 h); however, this did not affect lesion size or cell death within the first week after CHI. In contrast, by 2 and 4 weeks, a delayed reduction in lesion volume, macrophage accumulation, and astrogliosis were observed in the injured cortex and ipsilateral thalamus of CCL2−/− mice, corresponding to improved functional recovery as compared with wild-type mice after CHI. Our findings confirm the significant role of CCL2 in mediating post-traumatic secondary brain damage.     

Sports & exercise related traumatic brain injury in the Republic of Ireland – The neurosurgical perspective

BackgroundWhile the concerns regarding the long-term cognitive effects of repeated sports related head injury have become a major source of debate, it is not uncommon for these patients to require neurosurgical interventions in the acute setting. The aim of this study was to provide a unique insight into the acute nature and neurosurgical management of sports and exercise related traumatic brain injury.MethodsWe retrospectively analysed electronic records of all referrals made between July 2016 and December 2018 to the National Neurosurgical Centre at Beaumont Hospital to identify instances of sport and exercise related traumatic brain injuries (TBI). A sub-group analysis was carried out on patients transferred to the tertiary centre requiring neurosurgical/neuro-critical care.ResultsOver the 30-month period, 194 patients (mean age: 36) were referred with sports and exercise related TBI, of which 56 were transferred to our unit (26 adults, 30 paediatrics). The most frequently encountered sporting activities were cycling, gaelic football, horse riding and rugby. Injuries included cerebral contusions, subdural haematomas, extradural haematomas and skull fractures. Neurosurgical intervention via intracranial pressure monitoring (ICP), decompressive craniectomy and elevation of depressed skull fracture was required in 28 out of 194 patients (14.4%). 85.7% (n = 48) of patients had a discharge Glasgow Coma Scale (GCS) of 15. 4 patients had a tracheostomy in place at discharge and there were 4 mortalities.ConclusionsSports and exercise activities, ranging from contact team sports to individual activities, are a common cause of traumatic brain injury and maybe associated with a significant morbidity and mortality.     

Neuroprotective effect of (–)-epigallocatechin-3-gallate in rats when administered pre- or post-traumatic brain injury

Our previous study indicated that consuming (–)-epigallocatechin gallate (EGCG) before or after traumatic brain injury (TBI) eliminated free radical generation in rats, resulting in inhibition of neuronal degeneration and apoptotic death, and improvement of cognitive impairment. Here we investigated the effects of administering EGCG at various times pre- and post-TBI on cerebral function and morphology. Wistar rats were divided into five groups and were allowed access to (1) normal drinking water, (2) EGCG pre-TBI, (3) EGCG pre- and post-TBI, (4) EGCG post-TBI, and (5) sham-operated group with access to normal drinking water. TBI was induced with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3, and 7 days post-TBI, the number of 8-Hydroxy-2′-deoxyguanosine-, 4-Hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and levels of malondialdehyde around the damaged area were significantly decreased in all EGCG treatment groups compared with the water group (P < 0.05). Although there was a significant increase in the number of surviving neurons after TBI in each EGCG treatment group compared with the water group (P < 0.05), significant improvement of cognitive impairment after TBI was only observed in the groups with continuous and post-TBI access to EGCG (P < 0.05). These results indicate that EGCG inhibits free radical-induced neuronal degeneration and apoptotic death around the area damaged by TBI. Importantly, continuous and post-TBI access to EGCG improved cerebral function following TBI. In summary, consumption of green tea may be an effective therapy for TBI patients.     

Expression of brain nuclear factor-κB (P50) in mice with traumatic brain injury after hyperbaric oxygen treatment

Objective To investigate the relation between the therapeutic effect of hyperbaric oxygen treatment and nuclear factor-κB (NF-κB) (P50) expression in the brain tissue in mice with traumatic brain injury (TBI). Methods A total of 120 SD rats were randomly divided into sham-operated, TBI model, normobaric oxygen and hyperbaric oxygen (0.2 MPa) groups, and in the latter 3 groups, TBI was induced using Feeney's method. At 6 h and 1, 3, 5, and 7 d following TBI (6 rats at each time point), the rats were sacrificed to observe the pathological changes in the brain tissues under light microscope and detect the expression of NF-κB (P50) using immunohistochemistry. Results The rats in hyperbaric oxygen group showed lessened brain edema as compared with those in TBI model and normobaric oxygen groups. Only trace amount of NF-κB (P50) expression was observed in the sham-operated group, while in the 3 groups with TBI, NF-κB (P50) expression began to increase as early as 6 h after TBI and kept increasing till reaching the peak level at 5 days. At each of the time points for observation, the expression ofNF-κB (PS0) in hyperbaric oxygen group was significantly higher than those in TBI and normobaric oxygen groups (P<0.05). Conclusion Hyperbaric oxygen treatment offers protection of the injured neural cells and promotes their repair in rats following TBI. Increased NF-κB (P50) expression in the brain tissue may serve as one of the pathways mediating the neuroprotective effect of hyperbaric oxygen treatment.     

Depression-like and anxiety-like behavioural aftermaths of impact accelerated traumatic brain injury in rats: A model of comorbid depression and anxiety?

Depression and anxiety tend to be the most prevalent conditions among the multitude of neurobehavioural disorders which cause distress in the survivors of traumatic brain injury (TBI). The objective of the present investigation was to examine depression-like and anxiety-like behaviour of rats following diffuse TBI. Impact accelerated TBI was induced in anaesthetised rats by a modified weight drop method. TBI and sham-operated rats received either a chronic (14 days) regimen of escitalopram (5–20 mg/kg) or vehicle, following which they were subjected to a behavioural test battery. The results evince the depression-like behaviour of TBI rats in modified open field exploration, hyperemotionality, socio-sexual interaction and elevated plus-maze exploration paradigms. In addition, an anxiety-like behaviour was evident in social interaction and marble-burying tests. Chronic escitalopram (10 and 20 mg/kg) treatment significantly attenuated the TBI associated behavioural deficits. In conclusion, the aforesaid behavioural anomalies observed in TBI rats are analogous to comorbid anxiety and depression in humans. These findings substantiate the TBI rats as a candidate model of comorbid anxiety and depression.     

The incidence of traumatic brain injury in an adult population – how to classify mild cases?

Background: The incidence of traumatic brain injury (TBI) varies considerably between reports mainly because of variable methods used in recruiting of cases and especially in defining mild TBI. This study was carried out to evaluate the incidence in a given population according to published criteria for mild TBIs. Methods: All cases with symptoms of brain injury after a head trauma were collected from the health centres serving a defined population in South East Finland and from the one hospital taking care of all corresponding TBI cases. After reviewing the health records, the author classified the TBIs according to the guidelines of European Federation of Neurological Societies (EFNS). Results: A total of 370 patients were enrolled. The total crude annual incidence rate was 221 per 100.000 (95% CI: 176–265). A mild TBI was defined in 71% of the patients. According to the EFNS criteria, one‐third of them should be classified only with head traumas because of the lack of either loss consciousness (LOC) or post‐traumatic amnesia (PTA). This would reduce the total crude incidence rate to 137 per 100.000(95% CI: 101–172), an effect of the same magnitude as excluding mild TBIs treated out of hospital. Conclusions: The incidence rate falls within the wide range of previous published figures. Use of LOC or PTA as a criterion for mild TBI affects the incidence rate considerably as does the exclusion of mild cases treated out of hospital.     

Blood–brain barrier dysfunction following traumatic brain injury: correlation of Ktrans (DCE-MRI) and SUVR (99mTc-DTPA SPECT) but not serum S100B

Abstract

Objective:

Damage to the blood–brain barrier (BBB) is an important secondary mechanism that occurs following traumatic brain injury (TBI) and may provide a potential therapeutic target to improve patient outcome. For such a progress to be realised, an accurate assessment of BBB compromise needs to be established.

Methods:

Fourteen patients with TBI were prospectively recruited. Post-traumatic BBB dysfunction was assessed using dynamic contrast-enhanced MRI (DCE-MRI), single-photon emission computerised tomography (SPECT) and serum S100B levels.

Results:

A statistically significant correlation between standardised uptake value ratio (SUVR) calculated from 99mTc-DTPA SPECT and K^trans (a volume transfer constant) from DCE-MRI was found for those eight patients who had concurrent scans. The positive correlation persisted when the data were corrected for patient age, number of days following trauma and both parameters combined. We found no statistically significant correlation between either of the imaging modalities and concurrent serum S100B levels.

Discussion:

The correlation of SPECT with DCE-MRI suggests that either scan may be used to assess post-traumatic BBB damage. We could not support serum S100B to be an accurate measure of BBB damage when sampled a number of days following injury but the small number of patients, the heterogeneity in TBI patients and the delay following injury makes any firm conclusions regarding S100B and BBB difficult.     

Apolipoprotein E (APOE) ε4 genotype is associated with reduced neuropsychological performance in military veterans with a history of mild traumatic brain injury

Introduction: The purpose of this study was to investigate the effect of the apolipoprotein E (APOE) ε4 allele on neuropsychological functioning in military Veterans with a remote history of mild traumatic brain injury (mTBI).

Method: This cross-sectional study included 99 Veterans (mTBI = 53; military controls, MC = 46) who underwent neuropsychological assessment and APOE genotyping. Three neurocognitive composite scores—memory (α = .84), speed (α = .85), and executive functioning (α = .76)—were computed from 24 norm-referenced variables, and the total number of impaired scores (>1.5 SDs below mean) for each participant was calculated.

Results: Analyses of covariance adjusting for ethnicity and posttraumatic stress disorder (PTSD) symptoms revealed that although no significant differences were observed between mTBI ε4 allele groups on the executive functioning composite (p > .05), mTBI ε4+ Veterans performed more poorly than ε4? Veterans on the memory (p = .045, η_p² = .083) and speed (p = .023, η_p² = .106) composites. Furthermore, Mann–Whitney U tests showed that ε4+ mTBI Veterans displayed a significantly greater number of impaired scores than did ε4? mTBI Veterans (p = .010, r = .355). In contrast, there were no significant differences across any of the cognitive variables between ε4+ and ε4? MCs (all p > .05).

Conclusions: Results suggest that APOE ε4 genotype is related to reduced memory and processingspeed performance, as well as overall cognitive impairment, in those with a history of mTBI, but does not appear to have the same negative effects on cognition in the absence of neurotrauma. Although results are preliminary, the present study advances understanding of genetic influences on cognitive functioning in Veterans with remote mTBIs. Future longitudinal work is needed to elucidate the underlying brain-based mechanisms of ε4 allelic effects on cognitive and clinical outcomes following TBI.     

Marked increase of β-amyloid<Subscript>(1–42)</Subscript> and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury

Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimer's disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated beta-amyloid (Abeta), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of Abeta (Abeta1-42) and two soluble forms of APP (alpha-sAPP and ss-sAPP) in ventricular cerebrospinal fluid (VCSF) and Abeta(1-42) in plasma from 28 patients in a serial samples 0-11 days after TBI. The levels of alpha-sAPP, ss-sAPP and Abeta(1-42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-Abeta(1-42) up to 1173 % from day 0-1 to day 5-6 and in VCSF-beta-sAPP up to 2033 % increase from day 0-1 to day 7-11. There was also a slight but significant increase of VCSF-beta-sAPP from day 0-1 to day 5-6 and day 7-11. By contrast, the plasma- Abeta(1-42) level is unchanged after injury. The marked increase in VCSFAbeta(1-42) implies that increased Abeta expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-Abeta(1-42) in contrast to the marked increase in VCSF-Abeta(1-42) after severe TBI, supports the suggestion that plasma Abeta(1-42) does not reflect Abeta metabolism in the central nervous system (CNS).     

Experimental traumatic brain injury in rats stimulates the expression,production and activity of Alzheimer’s disease β-secretase (BACE-1)

Summary. Traumatic brain injury (TBI) is a risk factor for the development of Alzheimers disease (AD). After a traumatic brain injury depositions of amyloid beta (A) in the brain parenchyma were found. In this study we investigated the expression pattern of -secretase (BACE-1) in ipsi- or contralateral hippocampus and cortex following controlled cortical TBI in rats. BACE-1 mRNA levels, estimated by real time RT-PCR, were elevated 24h post injury, and persisting up to 72h, in the ipsi- and contralateral hippocampus and cerebral cortex as compared to the sham-treated animals (p<0.01). The TBI-induced changes in BACE-1 mRNA are due to enhanced hippocampal and cortical expression of BACE-1 mRNA in neurons and reactive astrocytes as revealed by in situ hybridization. The alterations in hippocampal BACE-1 mRNA levels are accompanied by corresponding increases in BACE-1 protein levels in ipsi- and contralateral hippocampus and ipsilateral cortex as demonstrated by Western blot analysis. In contrast, in the contralateral cortex only a weak increase of traumatically induced BACE-1 protein production was found. The activity of BACE-1 as measured by the formation of the cleavage product of amyloid beta precursor protein, transiently increased up to 48h after injury, but returned to basal level 7 days post injury. This study demonstrates that the -secretase is stimulated following TBI and may suggest a mechanism for the temporal increase of A levels observed in patients with brain trauma.     

Assessment of executive functions in children and adolescents with acquired brain injury (ABI) using a novel complex multi-tasking computerised task: The Jansari assessment of Executive Functions for Children (JEF-C©)

ABSTRACT

Objectives: The Jansari assessment of Executive Functions for Children (JEF-C^©) is a new non-immersive computerised assessment of executive functions. The objectives of the study were to test the feasibility and validity of JEF-C^© in children and adolescents with acquired brain injury (ABI).

Methods: Twenty-nine patients with ABI aged 10–18 years and 30 age-and gender-matched controls were tested. Participants performed JEF-C^©, Wechsler Abbreviated Scale of Intelligence (WASI) and the Behavioural Assessment of the Dysexecutive Syndrome for Children (BADS-C), while parents completed the Behaviour Rating Inventory of Executive Function (BRIEF) questionnaire.

Results: The JEF-C^© task proved feasible in patients with ABI. The internal consistency was medium (Cronbach’s alpha?=?0.62 and significant intercorrelations between individual JEF-C^© constructs). Patients performed significantly worse than controls on most of the JEF-C^© subscales and total score, with 41.4% of participants with ABI classified as having severe executive dysfunction. No significant correlations were found between JEF-C^© total score, the BRIEF indices, and the BADS-C. Significant correlations were found between JEF-C^© and demographic characteristics of the sample and intellectual ability, but not with severity/medical variables.

Conclusion: JEF-C^© is a playful complex task that appears to be a sensitive and ecologically valid assessment tool, especially for relatively high-functioning individuals.     

Pharmacological manipulation of peroxisome proliferator-activated receptor γ (PPARγ) reveals a role for anti-oxidant protection in a model of Parkinson's disease

Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to provide neuroprotection in a number of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. These protective effects are primarily considered to result from the anti-inflammatory actions of PPARγ, however, there is increasing evidence that anti-oxidant mechanisms may also contribute. This study explored the impact of the PPARγ agonist rosiglitazone and the PPARγ antagonist GW9662 in the MPP(+)/MPTP (1-methyl-4-phenylpyridinium/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease, focussing on oxidative stress mechanisms. Rosiglitazone attenuated reactive oxygen species formation induced by MPP(+) in SH-SY5Y cells concurrent with an upregulation of glutathione-S-transferase activity, but not superoxide dismutase activity. These responses were not attenuated by cotreatment with GW9662 suggesting that PPARγ activation is not required. The localisation of PPARγ in vivo to dopaminergic neurons of the substantia nigra pars compacta (SNpc) was established by immunohistochemistry and PPARγ levels were found to be upregulated 7 days after MPTP treatment. The importance of PPARγ in protecting against MPTP toxicity was confirmed by treating C57BL6 mice with GW9662. Treatment with GW9662 increased MPTP-induced neuronal loss in the SNpc whilst not affecting MPTP-induced reductions in striatal dopamine and 3,4-dihdroxyphenylacetic acid. GW9662 also caused neuronal loss in the SNpc of saline-treated mice. The evidence presented here supports the role of anti-oxidant mechanisms in the protective effects of PPARγ agonists in neurodegenerative diseases, but indicates that these effects may be independent of PPARγ activation. It also demonstrates the importance of PPARγ activity for neuronal survival within the SNpc.     

Loss of benefit in VIM thalamic deep brain stimulation (DBS) for essential tremor (ET): How prevalent is it?

Ventralis intermedius (Vim) thalamic deep brain stimulation for medication-refractory essential tremor (ET) has been shown to significantly improve severity of limb tremor in several large case series with significant reduction in objective motor scores. A variable proportion of patients experience decline in benefit over time, however, most studies have not been designed to describe the phenomenon of waning benefit in terms that are helpful for patient counseling. In this retrospective single center study, we define waning benefit as a phenomenon that occurs after patients begin to require reprogramming visits to optimize DBS benefit on tremor. We employed a survival analysis with time to escape (TTE) as a quantitative measure of time elapsed between implantation and the need for subsequent reprogramming. In our cohort of ET patients operated on with Vim DBS from 1994 to 2009, among 45 subjects who met inclusion criteria, 73% reported waning benefit at some point during a mean follow-up period of 56 months (range 12–152 months). The mean TTE from implantation date was 18 months (range 3–75 months). We conclude that loss of benefit over time from Vim DBS for ET is more prevalent than previously published estimates have indicated and should be discussed during patient counseling regarding durability of expected benefit. In addition, this data suggests that a disease-based explanation rather than technical factors are more likely to explain the decline in benefit.