| 1. |
- Aaro Jonsson, Catherine, et al.
(author)
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Cognitive Recovery and Development after Traumatic Brain Injury in Childhood : A Person-Oriented, Longitudinal Study
- 2013
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 30:2, s. 76-83
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Journal article (peer-reviewed)abstract
- Influence of childhood traumatic brain injury (TBI) on cognitive recovery and subsequent development is poorly understood. In this longitudinal study we used cluster analysis to explore acute stage individual profiles of injury age and cognition in 118 children with traumatic brain injury. Repeated measures of cognitive function were conducted at 30 months, indicating recovery, and 10 years post-injury, indicating development. Nine clusters were identified. Recovery was evident in three clusters, two of them with low functioning profiles. Developmental gains occurred for three clusters and an acute profile of higher freedom from distractibility (FFD) and lower processing speed (PS) was related to positive differences. One cluster, average low functioning and especially low verbal comprehension, demonstrated a slower development than peers. This suggests that developmental change after TBI in childhood takes place on a continuum, with both chance of long-term catching up, and risk of poor development. An acute profile of higher FFD and lower PS seemed to reflect injury consequences and were followed by developmental gains. These results challenge previous findings, and warrant further investigation.
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| 2. |
- Abu Hamdeh, Sami, et al.
(author)
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Differential DNA methylation of the genes for amyloid precursor protein, tau, and neurofilaments in human traumatic brain injury
- 2021
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 38:12, s. 1662-1669
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration; for example, amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM), and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients with iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH, and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828,888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation, and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain, and may have implications for the neurodegenerative disorders associated with TBI.
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| 3. |
- Abu Hamdeh, Sami, et al.
(author)
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Extended anatomical grading in diffuse axonal injury using MRI : Hemorrhagic lesions in the substantia nigra and mesencephalic tegmentum indicate poor long-term outcome
- 2017
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 5:34, s. 341-352
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Journal article (peer-reviewed)abstract
- Clinical outcome after traumatic diffuse axonal injury (DAI) is difficult to predict. In this study, three magnetic resonance imaging (MRI) sequences were used to quantify the anatomical distribution of lesions, to grade DAI according to the Adams grading system, and to evaluate the value of lesion localization in combination with clinical prognostic factors to improve outcome prediction. Thirty patients (mean 31.2 years ±14.3 standard deviation) with severe DAI (Glasgow Motor Score [GMS] <6) examined with MRI within 1 week post-injury were included. Diffusion-weighted (DW), T2*-weighted gradient echo and susceptibility-weighted (SWI) sequences were used. Extended Glasgow outcome score was assessed after 6 months. Number of DW lesions in the thalamus, basal ganglia, and internal capsule and number of SWI lesions in the mesencephalon correlated significantly with outcome in univariate analysis. Age, GMS at admission, GMS at discharge, and low proportion of good monitoring time with cerebral perfusion pressure <60 mm Hg correlated significantly with outcome in univariate analysis. Multivariate analysis revealed an independent relation with poor outcome for age (p = 0.005) and lesions in the mesencephalic region corresponding to substantia nigra and tegmentum on SWI (p = 0.008). We conclude that higher age and lesions in substantia nigra and mesencephalic tegmentum indicate poor long-term outcome in DAI. We propose an extended MRI classification system based on four stages (stage I—hemispheric lesions, stage II—corpus callosum lesions, stage III—brainstem lesions, and stage IV—substantia nigra or mesencephalic tegmentum lesions); all are subdivided by age (≥/<30 years).
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Al-Husseini, Ali, et al.
(author)
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Shorter Recovery Time in Concussed Elite Ice Hockey Players by Early Head-and-Neck Cooling: A Clinical Trial
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 40:11-12, s. 1075-1085
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Journal article (peer-reviewed)abstract
- A sports-related concussion (SRC) is most commonly sustained in contact sports, and is defined as a mild traumatic brain injury. An exercise-induced elevation of core body temperature is associated with increased brain temperature that may accelerate secondary injury processes following SRC, and exacerbate the brain injury. In a recent pilot study, acute head-neck cooling of 29 concussed ice hockey players resulted in shorter time to return-to-play. Here, we extended the clinical trial to include players of 19 male elite Swedish ice hockey teams over five seasons (2016-2021). In the intervention teams, acute head-neck cooling was implemented using a head cap for ≥45 min in addition to the standard SRC management used in controls. The primary endpoint was time from SRC until return-to-play (RTP). Sixty-one SRCs were included in the intervention group and 71 SRCs in the control group. The number of previous SRCs was 2 (median and interquartile range [IQR]: 1.0-2.0) and 1 (IQR 1.0-2.0) in the intervention and control groups, respectively; p = 0.293. Median time to initiate head-neck cooling was 10 min (IQR 7-15; range 5-30 min) and median duration of cooling was 45 min (IQR 45-50; range 45-70 min). The median time to RTP was 9 days in the intervention group (IQR 7.0-13.5 days) and 13 days in the control group (IQR 9-30; p < 0.001). The proportion of players out from play for more than the expected recovery time of 14 days was 24.7% in the intervention group, and 43.7% in controls (p < 0.05). Study limitations include that: 1) allocation to cooling or control management was at the discretion of the medical staff of each team, decided prior to each season, and not by strict randomization; 2) no sham cap was used and evaluations could not be performed by blinded assessors; and 3) it could not be established with certainty that injury severity was similar between groups. While the results should thus be interpreted with caution, early head-neck cooling, with the aim of attenuating cerebral hyperthermia, may reduce post-SRC symptoms and lead to earlier return-to-play in elite ice hockey players.
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| 8. |
- Alam, Aftab, et al.
(author)
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Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived Microglia
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 40:19-20, s. 2164-2173
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Journal article (peer-reviewed)abstract
- The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1 & beta;, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1 & beta; (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the in vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Bentzer, Peter, et al.
(author)
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Infusion of prostacyclin following experimental brain injury in the rat reduces cortical lesion volume
- 2001
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 18:3, s. 275-285
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Journal article (peer-reviewed)abstract
- Endothelial-derived prostacyclin is an important regulator of microvascular function, and its main actions are inhibition of platelet/leukocyte aggregation and adhesion, and vasodilation. Disturbances in endothelial integrity following traumatic brain injury (TBI) may result in insufficient prostacyclin production and participate in the pathophysiological sequelae of brain injury. The objective of this study was to evaluate the potential therapeutic effects of a low-dose prostacyclin infusion on cortical lesion volume, CA3 neuron survival and functional outcome following TBI in the rat. Anesthetized animals (sodium pentobarbital, 60 mg/kg, i.p.) were subjected to a lateral fluid percussion brain injury (2.5 atm) or sham injury. Following TBI, animals were randomized to receive a constant infusion of either prostacyclin (1 ng/kg x min(-1) i.v.) or vehicle over 48 h. All sham animals received vehicle (n = 6). Evaluation of neuromotor function, lesion volume, and CA3 neuronal loss was performed blindly. By 7 days postinjury, cortical lesion volume was significantly reduced by 43% in the prostacyclin-treated group as compared to the vehicle treated group (p < 0.01; n = 12 prostacyclin, n = 12 vehicle). No differences were observed in neuromotor function (48 h and 7 days following TBI), or in hippocampal cell loss (7 days following TBI) between the prostacyclin- and vehicle-treated groups. We conclude that prostacyclin in a low dose reduces loss of neocortical neurons following TBI and may be a potential clinical therapeutic agent to reduce neuronal cell death associated with brain trauma.
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| 14. |
- Bentzer, Peter, et al.
(author)
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Low-Dose Prostacyclin Improves Cortical Perfusion following Experimental Brain Injury in the Rat.
- 2003
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 20:5, s. 447-461
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Journal article (peer-reviewed)abstract
- It was recently shown that prostacyclin at a low dose reduces cortical cell death following brain trauma in the rat. Conceivably, prostacyclin with its vasodilatory, anti-aggregatory, anti-adhesive and permeability-reducing properties improved a compromised perfusion caused by post-traumatic vasoconstriction, microthrombosis and increased microvascular permeability. The objective of the present study was therefore to investigate the hemodynamic effects of low-dose prostacyclin in the traumatized rat cortex. Following a fluid percussion brain injury or a sham procedure, animals were treated with a continuous intravenous infusion of prostacyclin of 1 or 2 ng x kg(-1) x min(-1), or vehicle. Blood flow ([(14)C]-iodoantipyrine), the permeability-surface area product (PS) for [(51)Cr]-EDTA, and brain water content were measured after 3 or 48 h of treatment. Blood flow values in the injured cortex were transiently reduced to 0.42 +/- 0.2 mL x min(-1) in the vehicle group 3 h following trauma from a corresponding value of about 1.6 mL x min(-1) in the sham group, with recovery of blood flow after 48 h. Prostacyclin treatment caused a dose-dependent increase in blood flow which reached statistical significance 48 h following trauma. Brain water content and PS increased in the injured cortex post trauma and the higher dose of prostacyclin increased these parameters further at 48 h compared to the vehicle group (p < 0.05). The latter effects of prostacyclin cannot be attributed to an increase in permeability, as prostacyclin did not influence PS or brain water content following sham trauma. In fact prostacyclin has been shown to have permeability-decreasing properties. We conclude that prostacyclin improves cortical perfusion following brain trauma. The simultaneous aggravation of brain edema can be explained by an increased surface area, perhaps in combination with increased capillary hydrostatic pressure.
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| 15. |
- Bernick, Charles, et al.
(author)
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Longitudinal performance of plasma neurofilament light and tau in professional fighters: The Professional Fighters Brain Health Study.
- 2018
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In: Journal of neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 35:20
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Journal article (peer-reviewed)abstract
- The objective of this study is to evaluate longitudinal change in plasma neurofilament light (NF-L) and tau levels in relationship to clinical and radiological measures in professional fighters. Participants (active and retired professional fighters and control group) underwent annual blood sampling, 3 Tesla MRI brain imaging, computerized cognitive testing, and assessment of exposure to head trauma. Plasma tau and NF-L concentrations were measured using Simoa assays. Multiple linear regression models were used to compare the difference across groups in regard to baseline measurements, while mixed linear models was used for the longitudinal data with multiple measurements for each participant. Plasma samples were available on 471 participants. Baseline NF-L measures differed across groups (F_3,393=6.99, p=0.0001), with the active boxers having the highest levels. Higher NF-L levels at baseline were correlated with lower baseline MRI regional volumes and lower cognitive scores. The number of sparring rounds completed by the active fighters was correlated with NF-L (95% CI 0.0116-0.4053, p=0.0381), but not tau, levels. Among 126 subjects having multiple yearly samples, there was a significant difference in average yearly percentage change in tau across groups (F_3,83=3.87, p=0.0121).). We conclude that plasma NF-L and tau behave differently in a group of active and retired fighters; NF-L better reflects acute exposure whereas the role of plasma tau levels in signifying chronic change in brain structure over time requires further study.
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| 16. |
- Bernini, A., et al.
(author)
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Cerebral Metabolic Dysfunction at the Acute Phase of Traumatic Brain Injury Correlates with Long-Term Tissue Loss
- 2023
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 40:5-6, s. 472-481
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Journal article (peer-reviewed)abstract
- Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0-96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24-34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (-3.2% [-9.3 to -2.2] and -1.9% [-4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's rho = -0.68, p-value = 0.01) and low CMD glucose (rho = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI.
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| 17. |
- Bersch, Ines, et al.
(author)
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Motor Point Topography of Fundamental Grip Actuators in Tetraplegia: Implications in Nerve Transfer Surgery
- 2020
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 37:3, s. 441-447
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Journal article (peer-reviewed)abstract
- The differentiation between an upper motoneuron (UMN) lesion and lower motoneuron (LMN) lesion of forearm muscles in patients with tetraplegia is critical for the choice of treatment strategy. Specifically, the M. pronator teres (PT), M. flexor digitorum profundus III (FDPIII), and M. flexor pollicis longus (FPL) were studied since they represent key targets in nerve transfer surgery to restore grasp function. Forearm muscles of 24 patients with tetraplegia were tested bilaterally with electrical stimulation (ES) to determine whether UMN or LMN lesion was present. For detecting and testing the nerve stimulation points, a standardized mapping was developed and clinically applied. The relationship between the anatomical segmental spinal innervation and the innervation pattern tested by ES was determined. The data of 44 arms were analyzed. For PT, 19 arms showed an intact UMN, 18 arms an UMN lesion, and seven arms partial denervation. For FDPIII, three arms demonstrated an intact UMN, 26 arms an UMN lesion, 10 arms partial denervation, and five arms denervation. For FPL, two arms presented an intact UMN, 16 arms an UMN lesion, 12 arms partial denervation, and 14 arms denervation. A total of 20.1% ES tested muscles were partially denervated. In four patients, only one arm could be tested because of surgery-related limitations. According to the level of lesion and the segmental spinal innervation, most denervated muscles were present in the patient group C6 to C8. The ES, together with the developed mapping system, is reliable and can be recommended for standardized testing in surgery and rehabilitation. It offers the possibility to detect if and to what extent UMN and LMN lesions are present for the target muscles. It allows for refined pre-operative diagnostics and prognostics in spinal cord injury neurotization surgery.
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| 18. |
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| 19. |
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| 20. |
- Brophy, Gretchen M., et al.
(author)
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Biokinetic analysis of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in severe traumatic brain injury patient biofluids
- 2011
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 28:6, s. 861-870
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Journal article (peer-reviewed)abstract
- Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a neuron-specific enzyme that has been identified as a potential biomarker of traumatic brain injury (TBI). The study objectives were to determine UCH-L1 exposure and kinetic metrics, determine correlations between biofluids, and assess outcome correlations in severe TBI patients. Data were analyzed from a prospective, multicenter study of severe TBI (Glasgow Coma Scale [GCS] score ≤ 8). Cerebrospinal fluid (CSF) and serum data from samples taken every 6 h after injury were analyzed by enzyme-linked immunosorbent assay (ELISA). UCH-L1 CSF and serum data from 59 patients were used to determine biofluid correlations. Serum samples from 86 patients and CSF from 59 patients were used to determine outcome correlations. Exposure and kinetic metrics were evaluated acutely and up to 7 days post-injury and compared to mortality at 3 months. There were significant correlations between UCH-L1 CSF and serum median concentrations (r(s)=0.59, p<0.001), AUC (r(s)=0.3, p=0.027), Tmax (r(s)=0.68, p<0.001), and MRT (r(s)=0.65, p<0.001). Outcome analysis showed significant increases in median serum AUC (2016 versus 265 ng/mL*min, p=0.006), and Cmax (2 versus 0.4 ng/mL, p=0.003), and a shorter Tmax (8 versus 19 h, p=0.04) in those who died versus those who survived, respectively. In the first 24 h after injury, there was a statistically significant acute increase in CSF and serum median Cmax((0-24h)) in those who died. This study shows a significant correlation between UCH-L1 CSF and serum median concentrations and biokinetics in severe TBI patients, and relationships with clinical outcome were detected.
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| 21. |
- Büki, Andras, 1966-, et al.
(author)
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BIOMARKERS OF TRAUMATIC BRAIN- AND SPINAL CORD INJURY
- 2022
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 39:15-16, s. A7-A7
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Journal article (other academic/artistic)abstract
- Biomarkers of traumatic brain injury have long been investigated, yet their application in real life clinical practice is less than widespread.Research efforts under the umbrella of InTBIR and specifically CENTER TBI provided novel results based on a bulk of data collected.The symposium aims to provide an update on contemporary knowledge on purported clinical application of core biomarkers while also sharing novel data on emerging markers and novel technologies and approaches that may further improve our diagnostic and prognostic capabilities in the treatment of traumatic brain injury.The session will provide a critical review and update on biomarkers of spinal cord injury.
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| 22. |
- Büki, Andras, 1966-, et al.
(author)
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Postinjury cyclosporin a administration limits axonal damage and disconnection in traumatic brain injury
- 1999
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 16:6, s. 511-521
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Journal article (peer-reviewed)abstract
- Recent observations concerning presumed calcium-induced mitochondrial damage and focal intraaxonal proteolysis in the pathogenesis of traumatic axonal injury (TAI) have opened new perspectives for therapeutic intervention. Studies from our laboratory demonstrated that cyclosporin A (CsA), a potent inhibitor of Ca2+-induced mitochondrial damage, administered 30 min prior to traumatic brain injury preserved mitochondrial integrity in those axonal foci destined to undergo delayed disconnection. We attributed this neuroprotection to the inhibition by CsA of mitochondrial permeability transition (MPT). Additional experiments proved that CsA pretreatment also significantly reduced calcium-induced, calpain-mediated spectrin proteolysis (CMSP) and neurofilament compaction (NFC), pivotal events in the pathogenesis of axonal failure and disconnection. Given these provocative findings the goal of the current study was to evaluate the potential of CsA to inhibit calcium-induced axonal damage in a more clinically relevant postinjury treatment paradigm. To this end, cyclosporin A was administered intrathecally to Sprague Dawley rats 30 min following impact acceleration traumatic brain injury. The first group of animals were sacrificed 120 min postinjury and the density of CMSP and NFC immunoreactive damaged axonal segments of CsA-treated and vehicle-treated injured animals were quantitatively analyzed. A second group of CsA- versus vehicle-treated rats was sacrificed at 24 h postinjury to compare the density of damaged axons displaying beta amyloid precursor protein (APP) immunoreactivity, a signature protein of axonal perturbation and disconnection. Postinjury CsA administration resulted in a significant decrease (>60%) in CMSP/NFC immunoreactivity in corticospinal tracts and medial longitudinal fasciculi. A similar decrease was detected in the density of APP immunoreactive damaged axons, indicating an attenuation of axonal disconnection at 24 h postinjury in CsA-treated animals. These results once again suggest that the maintenance of the functional integrity of the mitochondria can prevent TAI, presumably via the preservation of the local energy homeostasis of the axon. Moreover and perhaps more importantly, these studies also demonstrate the efficacy of CsA administration when given in the early posttraumatic period. Collectively, our findings suggest that a therapeutic window exists for the use of drugs targeting mitochondria and energy regulation in traumatic brain injury.
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| 23. |
- Büki, Andras, 1966-, et al.
(author)
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Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury
- 2003
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In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 20:3, s. 261-268
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Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) evokes diffuse (traumatic) axonal injury (TAI), which contributes to morbidity and mortality. Damaged axons display progressive alterations gradually evolving to axonal disconnection. In severe TAI, the tensile forces of injury lead to a focal influx of Ca2+, initiating a series of proteolytic processes wherein the cysteine proteases, calpain and caspase modify the axonal cytoskeleton, causing irreversible damage over time postinjury. Although several studies have demonstrated that the systemic administration of calpain inhibitors reduces the extent of ischemic and traumatic contusional injury a direct beneficial effect on TAI has not been established to date. The current study was initiated to address this issue in an impact acceleration rat-TBI model in order to provide further evidence on the contribution of calpain-mediated proteolytic processes in the pathogenesis of TAI, while further supporting the utility of calpain-inhibitors. A single tail vein bolus injection of 30 mg/kg MDL-28170 was administered to Wistar rats 30 min preinjury. After injury the rats were allowed to survive 120 min when they were perfused with aldehydes. Brains were processed for immunohistochemical localization of damaged axonal profiles displaying either amyloid precursor protein (APP)- or RMO-14-immunoreactivity (IR), both considered markers of specific features of TAI. Digital data acquisition and statistical analysis demonstrated that preinjury administration of MDL-28170 significantly reduced the mean number of damaged RMO-14- as well as APP-IR axonal profiles in the brainstem fiber tracts analyzed. These results further underscore the role of calpain-mediated proteolytic processes in the pathogenesis of DAI and support the potential use of cell permeable calpain-inhibitors as a rational therapeutic approach in TBI.
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| 24. |
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| 25. |
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| 26. |
- Chesnut, Randall, et al.
(author)
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A Consensus-based Interpretation of the BEST TRIP ICP Trial.
- 2015
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 32:22, s. 1722-1724
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Journal article (peer-reviewed)abstract
- Widely varying published and presented analyses of the BEST TRIP randomized controlled trial of intracranial pressure (ICP) monitoring have suggested denying trial generalizability, questioning the need for ICP monitoring in severe traumatic brain injury (sTBI), re-assessing current clinical approaches to monitored ICP, and initiating a general ICP-monitoring moratorium. In response to this dissonance, 23 clinically-active, international opinion leaders in acute-care sTBI management met to draft a consensus statement to interpret this study. A Delphi-method-based approach employed iterative pre-meeting polling to codify the groups general opinions, followed by an in-person meeting wherein individual statements were refined. Statements required an agreement threshold of > 70% by blinded voting for approval. Seven precisely-worded statements resulted, with agreement levels of 83-100%. These statements, which should be read in toto to properly reflect the group's consensus positions, conclude that this study: 1) studied protocols, not ICP-monitoring per se; 2) applies only to those protocols and specific study groups and should not be generalized to other treatment approaches or patient groups; 3) strongly calls for further research on ICP interpretation and use; 4) should be applied cautiously to regions with much different treatment milieu; 5) did not investigate the utility of treating monitored ICP in the specific patient group with established intracranial hypertension; 6) should not change the practice of those currently monitoring ICP; and 7) provided a protocol, used in non-monitored study patients, that should be considered when treating without ICP monitoring. Consideration of these statements can clarify study interpretation and avoid "collateral damage".
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| 27. |
- Clausen, Fredrik, 1973-, et al.
(author)
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Acute Inflammatory Biomarker Responses to Diffuse Traumatic Brain Injury in the Rat Monitored by a Novel Microdialysis Technique
- 2019
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 36:2, s. 201-211
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Journal article (peer-reviewed)abstract
- Neuroinflammation is a major contributor to the progressive brain injury process induced by traumatic brain injury (TBI), and may play an important role in the pathophysiology of axonal injury. The immediate neuroinflammatory cascade cannot be characterized in the human setting. Therefore, we used the midline fluid percussion injury model of diffuse TBI in rats and a novel microdialysis (MD) method providing stable diffusion-driven biomarker sampling. Immediately post-injury, bilateral amphiphilic tri-block polymer coated MD probes (100 kDa cut off membrane) were inserted and perfused with Dextran 500 kDa-supplemented artificial cerebrospinal fluid (CSF) to optimize protein capture. Six hourly samples were analyzed for 27 inflammatory biomarkers (9 chemokines, 13 cytokines, and 5 growth factors) using a commercial multiplex biomarker kit. TBI (n = 6) resulted in a significant increase compared with sham-injured controls (n = 6) for five chemokines (eotaxin/CCL11, fractalkine/CX3CL1, LIX/CXCL5, monocyte chemoattractant protein [MCP]1α/CCL2, macrophage inflammatory protein [MIP]1α /CCL3), 10 cytokines (interleukin [IL]-1α, IL-1β, IL-4, IL-6, IL-10, IL-13, IL-17α, IL-18, interferon [IFN]-γ, tumor necrosis factor [TNF]-α), and four growth factors (epidermal growth factor [EGF], granulocyte-macrophage colony-stimulating factor [GM-CSF], leptin, vascular endothelial growth factor [VEGF]). Therefore, diffuse TBI was associated with an increased level of 18 of the 27 inflammatory biomarkers at one through six time points, during the observation period whereas the remaining 9 biomarkers were unaltered. The study shows that diffuse TBI induces an acute increase in a number of inflammatory biomarkers. The novel MD technique provides stable MD sampling suitable for further studies on the early neuroinflammatory cascade in TBI.
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| 28. |
- Clausen, Fredrik, et al.
(author)
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Interstitial F2-Isoprostane 8-Iso-PGF2α As a Biomarker of Oxidative Stress after Severe Human Traumatic Brain Injury
- 2012
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In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 29:5, s. 766-775
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Journal article (peer-reviewed)abstract
- Oxidative stress is a major contributor to the secondary injury process after experimental traumatic brain injury (TBI). The importance of oxidative stress in the pathobiology of human TBI is largely unknown. The F(2)-isoprostane 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)), synthesized in vivo through non-enzymatic free radical catalyzed peroxidation of arachidonic acid, is a widely used biomarker of oxidative stress in multiple disease states, including TBI and cerebral ischemia/reperfusion. Our hypothesis is that harvesting of biomarkers directly in the injured brain by cerebral microdialysis (MD) is advantageous because of its high spatial and temporal resolution compared to blood or cerebrospinal fluid sampling. The aim of this study was to test the feasibility of measuring 8-iso-PGF(2α) in MD, ventricular cerebrospinal fluid (vCSF), and plasma samples collected from patients with severe TBI, and to compare the MD signals with MD-glycerol, implicated as a biomarker of oxidative stress, as well as MD-glutamate, a biomarker of excitotoxicity. Six patients (4 men, 2 women) were included in the study, three of whom had a focal/mixed TBI, and three a diffuse axonal injury (DAI). Following the bedside analysis of routine MD biomarkers (glucose, lactate:pyruvate ratio, glycerol, and glutamate), two 12-h MD samples per day were used to analyze 8-iso-PGF(2α) from 24 h up to 8 days post-injury. The interstitial levels of 8-iso-PGF(2α) were markedly higher than the levels obtained from plasma and vCSF (p<0.05), supporting our hypothesis. The MD-8-iso-PGF(2α) levels correlated strongly (p<0.05) with MD-glycerol and MD-glutamate, which are widely used biomarkers of membrane phospholipid degradation/oxidative stress and excitotoxicity, respectively. This study demonstrates the feasibility of analyzing 8-iso-PGF(2α) in MD samples from the human brain. Our results support a close relationship between oxidative stress and excitotoxicity following human TBI. MD-8-iso-PGF(2α) in combination with MD-glycerol may be useful biomarkers of oxidative stress in the neurointensive care setting.
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| 29. |
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| 30. |
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| 31. |
- Clausen, Fredrik, et al.
(author)
-
T Lymphocyte trafficking : A novel target for neuroprotection in traumatic brain injury
- 2007
-
In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 24:8, s. 1295-1307
-
Journal article (peer-reviewed)abstract
- Infiltration of T lymphocytes is a key feature in transplant rejection and in several autoimmune disorders, but the role of T lymphocytes in traumatic brain injury (TBI) is largely unknown. Here we studied trafficking of immune cells in the brain after experimental TBI. We found that scavenging of reactive oxygen species (ROS) at the endothelial level dramatically reduced the infiltration of activated T lymphocytes. Immune cell infiltration was studied 12 h to 7 days after controlled cortical contusion in rats by ex vivo propagation of T lymphocytes (TcR+, CD8+), neutrophils (MPO+), and macrophages/microglia (ED-1+) from biopsies taken from injured cortex and analyzed by flow cytometry, as well as by quantitative immunohistochemistry. T lymphocyte and neutrophil infiltration peaked at 24 h and macrophages/microglia at 7 days post-injury. Pretreatment with 2-sulfophenyl-N-tert-butyl nitrone (S-PBN) produced a dramatic reduction of TcR+ T lymphocytes and a significantly smaller attenuation of neutrophil infiltration at 24 h post-injury, but did not affect CD8+ T lymphocytes or macrophages/microglia. S-PBN significantly reduced the expression of the endothelial adhesion molecules ICAM-1 and VCAM at 24 h for following TBI. We conclude that ROS inhibition at the endothelial level influenced T lymphocyte and neutrophil infiltration following TBI. We submit that the reduction of T lymphocyte infiltration is a key feature in improving TBI outcome after S-PBN treatment. Our data suggest that targeting T lymphocyte trafficking to the injured brain at the microvascular level is a novel concept of neuroprotection in TBI and warrants further exploration.
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| 32. |
- Clausen, Fredrik, 1973-, et al.
(author)
-
The nitrone free radical scavenger NXY-059 is neuroprotective when administered after traumatic brain injury in the rat
- 2008
-
In: Journal of Neurotrauma. - : Mary Ann Liebert, Inc.. - 0897-7151 .- 1557-9042. ; 25:12, s. 1449-1457
-
Journal article (peer-reviewed)abstract
- Reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI. NXY-059, a nitrone free radical trapping compound, has been shown to be neuroprotective in models of ischemic stroke but has not been evaluated in experimental TBI. In the present study, a continuous 24-h intravenous infusion of NXY-059 or vehicle was initiated 30min following a severe lateral fluid percussion brain injury (FPI) in adult rats (n=22), and histological and behavioral outcomes were evaluated. Sham-injured animals (n=22) receiving identical drug infusion were used as controls. Visuospatial learning was evaluated in the Morris water maze at post-injury days 11–14, followed by a probe trial (memory test) at day 18. The animals were sacrificed at day 18, and loss of hemispheric brain tissue was measured in microtubule-associated protein (MAP)–2stained sections. Brain-injured, NXY-059-treated animals showed a significant reduction of visuospatial learning deficits when compared to the brain-injured, vehicle-treated control animals (p<0.05). NXY-059-treated animals significantly reduced the loss of hemispheric tissue compared to brain-injured controls (43.0±11mm3 versus 74.4±19mm3, respectively; p<0.01). The results show that post-injury treatment with NXY-059 significantly attenuated the loss of injured brain tissue and improved cognitive outcome, suggesting a major role for ROS in the pathophysiology of TBI.
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| 33. |
- Cnossen, Maryse C., et al.
(author)
-
Prehospital Trauma Care among 68 European Neurotrauma Centers : Results of the CENTER-TBI Provider Profiling Questionnaires
- 2018
-
In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 36:1, s. 176-181
-
Journal article (peer-reviewed)abstract
- The first hour following traumatic brain injury (TBI) is considered crucial to prevent death and disability. It is, however, not established yet how the prehospital care should be organized to optimize recovery during the first hour. The objective of the current study was to examine variation in prehospital trauma care across Europe aiming to inform comparative effectiveness analyses on care for neurotrauma patients. A survey on prehospital trauma care was sent to 68 neurotrauma centers from 20 European countries participating in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. The survey was developed using literature review and expert opinion and was pilot tested in 16 centers. All participants completed the questionnaire. Advanced life support was used in half of the centers (n = 35; 52%), whereas the other centers used mainly basic life support (n = 26; 38%). A mobile medical team (MMT) could be dispatched 24/7 in most centers (n = 66; 97%). Helicopters were used in approximately half of the centers to transport the MMT to the scene (n = 39; 57%) and the patient to the hospital (n = 31, 46%). Half of the centers used a stay-and-play approach at the scene (n = 37; 55%), while the others used a scoop-and-run approach or another policy. We found wide variation in prehospital trauma care across Europe. This may reflect differences in socio-economic situations, geographic differences, and a general lack of strong evidence for some aspects of prehospital care. The current variation provides the opportunity to study the effectiveness of prehospital interventions and systems of care in comparative effectiveness research.
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| 34. |
- Cseplo, Peter, et al.
(author)
-
Hemolyzed Blood Elicits a Calcium Antagonist and High CO2 Reversible Constriction via Elevation of [Ca2+]i in Isolated Cerebral Arteries
- 2017
-
In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 34:2, s. 529-534
-
Journal article (peer-reviewed)abstract
- During acute subarachnoid hemorrhage, blood is hemolyzed, which is followed by a significant cerebrovascular spasm resulting in a serious clinical condition. Interestingly, however, the direct vasomotor effect of perivascular hemolyzed blood (HB) has not yet been characterized, preventing the assessment of contribution of vasoconstrictor mechanisms deriving from brain tissue and/or blood and development of possible treatments. We hypothesized that perivascular HB reduces the diameter of the cerebral arteries (i.e., basilar artery [BA]; middle cerebral artery [MCA]) by elevating vascular tissue [Ca2+](i) level. Vasomotor responses were measured by videomicroscopy and intracellular Ca2+ by the Fura2-AM ratiometric method. Adding HB to the vessel chamber reduced the diameter significantly (BA: from 264 +/- 7 to 164 +/- 11 mu m; MCA: from 185 +/- 15 to 155 +/- 14 mu m), which was reversed to control level by wash-out of HB. Potassium chloride (KCl), HB, serum, hemolyzed red blood cell (RBC), plasma, and platelet suspension (PLTs) elicited significant constrictions of isolated basilar arteries. There was a significant increase in K+ concentration in hemolyzed HB (7.02 +/- 0.22 mmol/L) compared to Krebs' solution (6.20 +/- 0.01 mmol/L). Before HB, acetylcholine (ACh), sodium-nitroprussid (SNP), nifedipin, and CO2 elicited substantial dilations in cerebral arteries. In contrast, in the presence of HB dilations to ACh, SNP decreased, but not to nifedipine and CO2. After washout of HB, nitric oxide-mediated dilations remained significantly reduced compared to control. HB significantly increased the ratiometric Ca signal, which returned to control level after washout. In conclusion, perivascular hemolyzed blood elicits significant-nifedipine and high CO2 reversible-constrictions of isolated BAs and MCAs, primarily by increasing intracellular Ca2+, findings that can contribute to the refinement of local treatment of subarachnoid hemorrhage.
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| 35. |
- Czeiter, Endre, et al.
(author)
-
Brain Injury Biomarkers May Improve the Predictive Power of the IMPACT Outcome Calculator
- 2012
-
In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 29:9, s. 1770-1778
-
Journal article (peer-reviewed)abstract
- Outcome prediction following severe traumatic brain injury (sTBI) is a widely investigated field of research. A major breakthrough is represented by the IMPACT prognostic calculator based on admission data of more than 8500 patients. A growing body of scientific evidence has shown that clinically meaningful biomarkers, including glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), and alpha II-spectrin breakdown product (SBDP145), could also contribute to outcome prediction. The present study was initiated to assess whether the addition of biomarkers to the IMPACT prognostic calculator could improve its predictive power. Forty-five sTBI patients (GCS score <= 8) from four different sites were investigated. We utilized the core model of the IMPACT calculator (age, GCS motor score, and reaction of pupils), and measured the level of GFAP, UCH-L1, and SBDP145 in serum and cerebrospinal fluid (CSF). The forecast and actual 6-month outcomes were compared by logistic regression analysis. The results of the core model itself, as well as serum values of GFAP and CSF levels of SBDP145, showed a significant correlation with the 6-month mortality using a univariate analysis. In the core model, the Nagelkerke R-2 value was 0.214. With multivariate analysis we were able to increase this predictive power with one additional biomarker (GFAP in CSF) to R-2 = 0.476, while the application of three biomarker levels (GFAP in CSF, GFAP in serum, and SBDP145 in CSF) increased the Nagelkerke R-2 to 0.700. Our preliminary results underline the importance of biomarkers in outcome prediction, and encourage further investigation to expand the predictive power of contemporary outcome calculators and prognostic models in TBI.
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| 36. |
- Czeiter, Endre, et al.
(author)
-
Traumatic axonal injury in the spinal cord evoked by traumatic brain injury
- 2008
-
In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 25:3, s. 205-213
-
Journal article (peer-reviewed)abstract
- Although it is well known that traumatic brain injury (TBI) evokes traumatic axonal injury (TAI) within the brain, TBI-induced axonal damage in the spinal cord (SC) has been less extensively investigated. Detection of such axonal injury in the spinal cord would further the complexity of TBI while also challenging some functional neurobehavioral endpoints frequently used to assess recovery in various models of TBI. To assess TAI in the spinal cord associated with TBI, we analyzed the craniocervical junction (CCJ), cervico-thoracic (CT), and thoraco-lumber (ThL) spinal cord in a rodent model of impact acceleration of TBI of varying severities. Rats were transcardially fixed with aldehydes at 2, 6, and 24 h post-injury (n = 36); each group included on sham-injured rodent. Semi-serial vibratome sections were reacted with antibodies targeting TAI via alteration in cytoskeletal integrity or impaired axonal transport. Consistent with previous observations in this model, the CCJ contained numerous injured axons. Immunoreactive, damaged axonal profiles were also detected as caudal, as the ThL spinal cord displayed morphological characteristics entirely consistent with those described in the brainstem and the CCJ. Quantitative analyses demonstrated that the occurrence and extent of TAI is positively associated with the impact/energy of injury and negatively with the distance from the brainstem. These observations show that TBI can evoke TAI in regions remote from the injury site, including the spinal cord itself. This finding is relevant to shaken baby syndrome as well as during the analysis of data in functional recovery in various models of TBI.
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| 37. |
- Czigler, Andras, et al.
(author)
-
Hypertension exacerbates cerebrovascular oxidative stress induced by mild traumatic brain injury : Protective effects of the Mitochondria-Targeted Antioxidative Peptide SS-31
- 2019
-
In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 36:23, s. 3309-3315
-
Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. Because hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive and spontaneously hypertensive rats (SHR) and assessed changes in cytoplasmic and mitochondrial superoxide (O2-) production by confocal microscopy in isolated middle cerebral arteries (MCA) 2 weeks after mTBI using dihydroethidine (DHE) and the mitochondria-targeted redox-sensitive fluorescent indicator dye MitoSox. We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O2- production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg-1 day-1, i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.
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| 38. |
- Dams-O'Connor, Kristen, et al.
(author)
-
Alzheimer's Disease-Related Dementias Summit 2019: National Research Priorities for the Investigation of Traumatic Brain Injury as a Risk Factor for Alzheimer's Disease and Related Dementias.
- 2021
-
In: Journal of neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 38:23, s. 3186-3194
-
Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) is a risk factor for later-life dementia. Clinical and pre-clinical studies have elucidated multiple mechanisms through which TBI may influence or exacerbate multiple pathological processes underlying Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). The National Institutes of Health hosts triennial ADRD Summits to inform a national research agenda, and the 2019 ADRD Summit was the first to highlight "TBI and AD/ADRD Risk" as an emerging topic in the field. A multidisciplinary committee of TBI researchers with relevant expertise reviewed extant literature, identified research gaps and opportunities, and proposed draft research recommendations at the 2019 ADRD Summit. These research recommendations, further refined after broad stakeholder input at the Summit, cover four overall areas: 1) Encourage crosstalk and interdisciplinary collaboration between TBI and dementia researchers; 2) Establish infrastructure to study TBI as a risk factor for AD/ADRD; 3) Promote basic and clinical research examining the development and progression of TBI AD/ADRD neuropathologies and associated clinical symptoms; and 4) Characterize the clinical phenotype of progressive dementia associated with TBI and develop non-invasive diagnostic approaches. These recommendations recognize a need to strengthen communication and build frameworks to connect the complexity of TBI with rapidly evolving AD/ADRD research. Recommendations acknowledge TBI as a clinically and pathologically heterogeneous disease whose associations with AD/ADRDs remain incompletely understood. The recommendations highlight the scientific advantage of investigating AD/ADRD in the context of a known TBI exposure, the study of which can directly inform on disease mechanisms and treatment targets for AD/ADRDs with shared common pathways.
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| 39. |
- Dams-O'Connor, K., et al.
(author)
-
Alzheimer's Disease-Related Dementias Summit 2022: National Research Priorities for the Investigation of Post-Traumatic Brain Injury Alzheimer's Disease and Related Dementias
- 2023
-
In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 40:15-16, s. 1512-1523
-
Journal article (peer-reviewed)abstract
- Traumatic Brain Injury (TBI) is a risk factor for Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) and otherwise classified post-traumatic neurodegeneration (PTND). Targeted research is needed to elucidate the circumstances and mechanisms through which TBI contributes to the initiation, development, and progression of AD/ADRD pathologies including multiple etiology dementia (MED). The National Institutes of Health hosts triennial ADRD summits to inform a national research agenda, and TBI was included for a second time in 2022. A multidisciplinary expert panel of TBI and dementia researchers was convened to re-evaluate the 2019 research recommendations for understanding TBI as an AD/ADRD risk factor and to assess current progress and research gaps in understanding post-TBI AD/ADRD. Refined and new recommendations were presented during the MED special topic session at the virtual ADRD Summit in March 2022. Final research recommendations incorporating broad stakeholder input are organized into four priority areas as follows: (1) Promote interdisciplinary collaboration and data harmonization to accelerate progress of rigorous, clinically meaningful research; (2) Characterize clinical and biological phenotypes of PTND associated with varied lifetime TBI histories in diverse populations to validate multimodal biomarkers; (3) Establish and enrich infrastructure to support multimodal longitudinal studies of individuals with varied TBI exposure histories and standardized methods including common data elements (CDEs) for ante-mortem and post-mortem clinical and neuropathological characterization; and (4) Support basic and translational research to elucidate mechanistic pathways, development, progression, and clinical manifestations of post-TBI AD/ADRDs. Recommendations conceptualize TBI as a contributor to MED and emphasize the unique opportunity to study AD/ADRD following known exposure, to inform disease mechanisms and treatment targets for shared common AD/ADRD pathways.
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| 40. |
- Darragh, Walsh, et al.
(author)
-
Mechanical Properties of the Cranial Meninges: A Systematic Review
- 2021
-
In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 38:13, s. 1748-1761
-
Journal article (peer-reviewed)abstract
- The meninges are membranous tissues that are pivotal in maintaining homeostasis of the central nervous system. Despite the importance of the cranial meninges in nervous system physiology and in head injury mechanics, our knowledge of the tissues' mechanical behavior and structural composition is limited. This systematic review analyzes the existing literature on the mechanical properties of the meningeal tissues. Publications were identified from a search of Scopus, Academic Search Complete, and Web of Science and screened for eligibility according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review details the wide range of testing techniques employed to date and the significant variability in the observed experimental findings. Our findings identify many gaps in the current literature that can serve as a guide for future work for meningeal mechanics investigators. The review identifies no peer-reviewed mechanical data on the falx and tentorium tissues, both of which have been identified as key structures in influencing brain injury mechanics. A dearth of mechanical data for the pia-arachnoid complex also was identified (no experimental mechanics studies on the human pia-arachnoid complex were identified), which is desirable for biofidelic modeling of human head injuries. Finally, this review provides recommendations on how experiments can be conducted to allow for standardization of test methodologies, enabling simplified comparisons and conclusions on meningeal mechanics.
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| 41. |
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| 42. |
- DeWitt, Douglas S., et al.
(author)
-
Pre-clinical testing of therapies for traumatic brain injury
- 2018
-
In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 35:23, s. 2737-2754
-
Journal article (peer-reviewed)abstract
- Despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials. To develop recommendations and guidelines for pre-clinical testing of pharmacological or biological therapies for TBI, the Moody Project for Translational Traumatic Brain Injury Research hosted a symposium attended by investigators with extensive experience in pre-clinical TBI testing. The symposium participants discussed issues related to pre-clinical TBI testing including experimental models, therapy and outcome selection, study design, data analysis, and dissemination. Consensus recommendations included the creation of a manual of standard operating procedures with sufficiently detailed descriptions of modeling and outcome measurement procedures to permit replication. The importance of the selection of clinically relevant outcome variables, especially related to behavior testing, was noted. Considering the heterogeneous nature of human TBI, evidence of therapeutic efficacy in multiple, diverse (e.g., diffuse vs. focused) rodent models and a species with a gyrencephalic brain prior to clinical testing was encouraged. Basing drug doses, times, and routes of administration on pharmacokinetic and pharmacodynamic data in the test species was recommended. Symposium participants agreed that the publication of negative results would reduce costly and unnecessary duplication of unsuccessful experiments. Although some of the recommendations are more relevant to multi-center, multi-investigator collaborations, most are applicable to pre-clinical therapy testing in general. The goal of these consensus guidelines is to increase the likelihood that therapies that improve outcomes in pre-clinical studies will also improve outcomes in TBI patients.
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| 43. |
- Dickens, Alex Mountfort, et al.
(author)
-
Serum Metabolites Associated with Computed TomographyFindings after Traumatic Brain Injury
- 2018
-
In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 35:22, s. 2673-2683
-
Journal article (peer-reviewed)abstract
- There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish between different types of injuries observed. Logistic regression models using metabolite data from the discovery cohort (n=144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and negative findings on head CT. The resultant models were then tested in the validation cohort (n=66, Cambridge, UK). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (AUC=0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC=0.77 in Turku patients and AUC=0.73 in Cambridge patients). Furthermore, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC=0.87 in Turku patients and AUC=0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.
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| 44. |
- Dijkland, Simone A., et al.
(author)
-
Outcome Prediction after Moderate and Severe Traumatic Brain Injury : External Validation of Two Established Prognostic Models in 1742 European Patients
- 2021
-
In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 38:10, s. 1377-1388
-
Journal article (peer-reviewed)abstract
- The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models predict functional outcome after moderate and severe traumatic brain injury (TBI). We aimed to assess their performance in a contemporary cohort of patients across Europe. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study is a prospective, observational cohort study in patients presenting with TBI and an indication for brain computed tomography. The CENTER-TBI core cohort consists of 4509 TBI patients available for analyses from 59 centers in 18 countries across Europe and Israel. The IMPACT validation cohort included 1173 patients with GCS ≤12, age ≥14, and 6-month Glasgow Outcome Scale-Extended (GOSE) available. The CRASH validation cohort contained 1742 patients with GCS ≤14, age ≥16, and 14-day mortality or 6-month GOSE available. Performance of the three IMPACT and two CRASH model variants was assessed with discrimination (area under the receiver operating characteristic curve; AUC) and calibration (comparison of observed vs. predicted outcome rates). For IMPACT, model discrimination was good, with AUCs ranging between 0.77 and 0.85 in 1173 patients and between 0.80 and 0.88 in the broader CRASH selection (n = 1742). For CRASH, AUCs ranged between 0.82 and 0.88 in 1742 patients and between 0.66 and 0.80 in the stricter IMPACT selection (n = 1173). Calibration of the IMPACT and CRASH models was generally moderate, with calibration-in-the-large and calibration slopes ranging between -2.02 and 0.61 and between 0.48 and 1.39, respectively. The IMPACT and CRASH models adequately identify patients at high risk for mortality or unfavorable outcome, which supports their use in research settings and for benchmarking in the context of quality-of-care assessment.
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| 45. |
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| 46. |
- Dyhrfort, Philip, et al.
(author)
-
Monitoring of Protein Biomarkers of Inflammation in Human Traumatic Brain Injury Using Microdialysis and Proximity Extension Assay Technology in Neurointensive Care
- 2019
-
In: Journal of Neurotrauma. - : MARY ANN LIEBERT, INC. - 0897-7151 .- 1557-9042. ; 36:20, s. 2872-2885
-
Journal article (peer-reviewed)abstract
- Traumatic brain injury (TBI) is followed by secondary injury mechanisms strongly involving neuroinflammation. To monitor the complex inflammatory cascade in human TBI, we used cerebral microdialysis (MD) and multiplex proximity extension assay (PEA) technology and simultaneously measured levels of 92 protein biomarkers of inflammation in MD samples every three hours for five days in 10 patients with severe TBI under neurointensive care. One mu L MD samples were incubated with paired oligonucleotide-conjugated antibodies binding to each protein, allowing quantification by real-time quantitative polymerase chain reaction. Sixty-nine proteins were suitable for statistical analysis. We found five different patterns with either early (<48 h; e.g., CCL20, IL6, LIF, CCL3), mid (48-96 h; e.g., CCL19, CXCL5, CXCL10, MMP1), late (>96 h; e.g., CD40, MCP2, MCP3), biphasic peaks (e.g., CXCL1, CXCL5, IL8) or stable (e.g., CCL4, DNER, VEGFA)/low trends. High protein levels were observed for e.g., CXCL1, CXCL10, MCP1, MCP2, IL8, while e.g., CCL28 and MCP4 were detected at low levels. Several proteins (CCL8, -19, -20, -23, CXCL1, -5, -6, -9, -11, CST5, DNER, Flt3L, and SIRT2) have not been studied previously in human TBI. Cross-correlation analysis revealed that LIF and CXCL5 may play a central role in the inflammatory cascade. This study provides a unique data set with individual temporal trends for potential inflammatory biomarkers in patients with TBI. We conclude that the combination of MD and PEA is a powerful tool to map the complex inflammatory cascade in the injured human brain. The technique offers new possibilities of protein profiling of complex secondary injury pathways.
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| 47. |
- Ekmark-Lewén, Sara, et al.
(author)
-
The Multivariate Concentric Square Field Test Reveals Behavioral Profiles of Risk Taking, Exploration, and Cognitive Impairment in Mice Subjected to Traumatic Brain Injury
- 2010
-
In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 27:9, s. 1643-1655
-
Journal article (peer-reviewed)abstract
- There is a need for more efficient tests to evaluate functional outcome following experimental traumatic brain injury (TBI), reflecting deficits in cognitive, sensory, and motor functions that are seen in TBI patients. The Multivariate Concentric Square Field (TM) (MCSF) test is a relatively new behavioral model that measures exploration, risk taking, risk assessment, and shelter seeking, all of which are evolutionarily-conserved strategies for survival. The multivariate design enables scoring of different functional domains in a single test situation, with a free choice of optional environmental settings. Furthermore, repeated trials permits cognitive effects to be measured. In the present study, 11 anesthetized C57BL6 mice received controlled cortical injury (CCI) (0.5mm and 3.3 m/sec) over the right parietal cerebral cortex or sham surgery (n - 12). Naive mice (n 12) not subjected to any surgical procedure were also included. The animals were evaluated in the MCSF test at 2 and 7 days post-surgery, and behavioral profiles were analyzed. The results revealed differences in risk taking and explorative behavior between the sham animals and the animals subjected to trauma. Animals subjected to trauma were characterized by taking more risks and had a higher level of exploration activity, but they sought less shelter. Repeated exposure to the MCSF caused a general decrease in activity in the naive and sham group, while a more specific behavioral impairment was seen in injured mice, suggesting cognitive dysfunction. We submit that the MCSF test is a useful complementary tool for functional outcome evaluation in experimental TBI.
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| 48. |
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| 49. |
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| 50. |
- Falci, S, et al.
(author)
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Obliteration of a posttraumatic spinal cord cyst with solid human embryonic spinal cord grafts : first clinical attempt.
- 1997
-
In: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 14, s. 875-
-
Journal article (peer-reviewed)abstract
- Cystic lesions of the spinal cord (syringomyelia) may occur after spinal cord injury. Posttraumatic syringomyelia may result in a myelopathy causing symptoms of sensory and motor loss, as well as worsening spasticity, pain, hyperhidrosis, and autonomic dysreflexia. Shunting of the cyst cavity along with untethering of the scarred spinal cord is widely accepted as the treatment of choice. However, the long-term stabilization of the progressive myelopathy caused by a posttraumatic cyst is suboptimal because of arachnoidal rescarring, shunt tube blockage, and cyst reexpansion. A new neurosurgical strategy to overcome the complication of cyst reexpansion was designed. Experimental studies have shown the successful use of embryonic spinal cord grafts, including human grafts, to obliterate induced spinal cord cavities in rats. The authors report the first use of solid human embryonic spinal cord grafts to successfully obliterate 6 cm of a large cyst cavity in a patient becoming myelopathic from a posttraumatic cyst. The grafts are well visualized by MRI to the 7-month postoperative follow-up and cyst obliteration is seen in the region where the grafts were placed.
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