Endre Czeiter

Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: A case control study

IntroductionAuthors of several studies have studied biomarkers and computed tomography (CT) findings in the acute phase after severe traumatic brain injury (TBI). However, the correlation between structural damage as assessed by neuroimaging and biomarkers has not been elucidated. The aim of this study was to investigate the relationships among neuronal (Ubiquitin carboxy-terminal hydrolase L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels in serum, neuroradiological findings and outcomes after severe TBI.MethodsThe study recruited patients from four neurotrauma centers. Serum samples for UCH-L1 and GFAP were obtained at the time of hospital admission and every 6 hours thereafter. CT scans of the brain were obtained within 24hrs of injury. Outcome was assessed by Glasgow Outcome Scale (GOS) at discharge and at 6 months.Results81 severe TBI patients and 167 controls were enrolled. The mean serum levels of UCH-L1 and GFAP were higher (p < 0.001) in TBI patients compared to controls. UCH-L1 and GFAP serum levels correlated significantly with Glasgow Coma Scale (GCS) and CT findings. GFAP levels were higher in patients with mass lesions than in those with diffuse injury (2.95 ± 0.48 ng/ml versus 0.74 ± 0.11 ng/ml) while UCH-L1 levels were higher in patients with diffuse injury (1.55 ± 0.18 ng/ml versus 1.21 ± 0.15 ng/ml, p = 0.0031 and 0.0103, respectively). A multivariate logistic regression showed that UCH-L1 was the only independent predictor of death at discharge [adjusted odds ratios 2.95; 95% confidence interval, 1.46-5.97], but both UCH-L1 and GFAP levels strongly predicted death 6 months post-injury.ConclusionsRelationships between structural changes detected by neuroimaging and biomarkers indicate each biomarker may reflect a different injury pathway. These results suggest that protein biomarkers could provide better characterization of subjects at risk for specific types of cellular damage than that obtained with neuroimaging alone, as well as provide valuable information about injury severity and outcome after severe TBI.

Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics

PurposeThis review summarizes protein biomarkers in mild and severe traumatic brain injury in adults and children and presents a strategy for conducting rationally designed clinical studies on biomarkers in head trauma.MethodsWe performed an electronic search of the National Library of Medicine’s MEDLINE and Biomedical Library of University of Pennsylvania database in March 2008 using a search heading of traumatic head injury and protein biomarkers. The search was focused especially on protein degradation products (spectrin breakdown product, c-tau, amyloid-β1–42) in the last 10xa0years, but recent data on “classical” markers (S-100B, neuron-specific enolase, etc.) were also examined.ResultsWe identified 85 articles focusing on clinical use of biomarkers; 58 articles were prospective cohort studies with injury and/or outcome assessment.ConclusionsWe conclude that only S-100B in severe traumatic brain injury has consistently demonstrated the ability to predict injury and outcome in adults. The number of studies with protein degradation products is insufficient especially in the pediatric care. Cohort studies with well-defined end points and further neuroproteomic search for biomarkers in mild injury should be triggered. After critically reviewing the study designs, we found that large homogenous patient populations, consistent injury, and outcome measures prospectively determined cutoff values, and a combined use of different predictors should be considered in future studies.

Brain Injury Biomarkers May Improve the Predictive Power of the IMPACT Outcome Calculator

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 αII-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.

Glial Neuronal Ratio: A Novel Index for Differentiating Injury Type in Patients with Severe Traumatic Brain Injury

Neurobiochemical marker levels in blood after traumatic brain injury (TBI) may reflect structural changes detected by neuroimaging. This study evaluates whether correlations between neuronal (ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarkers may be used as an indicator for differing intracranial pathologies after brain trauma. In 59 patients with severe TBI (Glasgow Coma Scale [GCS] score≤8) serum samples were obtained at the time of hospital admission and analyzed for UCH-L1 and GFAP. Glial neuronal ratio (GNR) was evaluated as the ratio between GFAP and UCH-L1 concentrations. A logistic regression analysis was used to identify variables associated with type of injury. GNR had a median of 0.85 and was positively correlated with age (R=0.45, p=0.003). Twenty-nine patients presented with diffuse injury and 30 with focal mass lesions as assessed by CT scan at admission and classified according to the Marshall Classification. GNR was significantly higher in the focal mass lesion group compared with the diffuse injury group (1.77 versus 0.48, respectively; p=0.003). Receiver operating characteristic curve analysis showed that GNR discriminated between types of injury (area under the curve [AUC]=0.72; p=0.003). GNR was more accurate earlier (≤12u2009h after injury) than later (AUC=0.80; p=0.002). Increased GNR was independently associated with type of injury, but not age, gender, GCS score, or mechanism of injury. GNR was significantly higher in patients who died, but was not an independent predictor of death. The data from the present study indicate that GNR provides valuable information about different injury pathways, which may be of diagnostic significance. In addition, GNR may help to identify different pathophysiological mechanisms following different types of brain trauma, with implications for therapeutic interventions.

Effect of PACAP in Central and Peripheral Nerve Injuries

Pituitary adenylate cyclase activating polypeptide (PACAP) is a bioactive peptide with diverse effects in the nervous system. In addition to its more classic role as a neuromodulator, PACAP functions as a neurotrophic factor. Several neurotrophic factors have been shown to play an important role in the endogenous response following both cerebral ischemia and traumatic brain injury and to be effective when given exogenously. A number of studies have shown the neuroprotective effect of PACAP in different models of ischemia, neurodegenerative diseases and retinal degeneration. The aim of this review is to summarize the findings on the neuroprotective potential of PACAP in models of different traumatic nerve injuries. Expression of endogenous PACAP and its specific PAC1 receptor is elevated in different parts of the central and peripheral nervous system after traumatic injuries. Some experiments demonstrate the protective effect of exogenous PACAP treatment in different traumatic brain injury models, in facial nerve and optic nerve trauma. The upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central and peripheral nerve injuries show the important function of PACAP in neuronal regeneration indicating that PACAP may also be a promising therapeutic agent in injuries of the nervous system.

Determination of cerebrospinal fluid concentrations of arginine and dimethylarginines in patients with subarachnoid haemorrhage

Elevated cerebrospinal fluid (CSF) concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), are assumed to be related to delayed vasospasm after subarachnoid haemorrhage (SAH). However, data on CSF concentrations of L-arginine, ADMA and its structural isomer symmetric dimethylarginine (SDMA) are very sparse in humans. We here present a new hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS-MS) method for the precise determination of these substances in CSF. The method requires only minimal sample preparation and features isotope labeled internal standards. First data of patients with SAH showed that on the day of admission CSF concentration values of L-arginine and ADMA were not significantly different from controls, but increased markedly during the course of the hospital stay. The decrease of the L-arginine to ADMA ratio points to a progressive impairment of the NO production rate in the brain after SAH which is confirmed by a simultaneous decrease in nitrate and nitrite concentrations in CSF.

Traumatic axonal injury in the spinal cord evoked by traumatic brain injury

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.

Rescuing neurons and glia: is inhibition of apoptosis useful?

Traumatic brain injury (TBI) represents a leading cause of death in western countries. Despite all research efforts we still lack any pharmacological agent that could effectively be utilized in the clinical treatment of TBI. Detailed unraveling of the pathobiological processes initiated by/operant in TBI is a prerequisite to the development of rational therapeutic interventions. In this review we provide a summary of those therapeutic interventions purported to inhibit the cell death (CD) cascades ignited in TBI. On noxious stimuli three major forms of CD, apoptosis, autophagia and necrosis may occur. Apoptosis can be induced either via the mitochondrial (intrinsic) or the receptor mediated (extrinsic) pathway; endoplasmic reticular stress is the third trigger of caspase-mediated apoptotic processes. Although, theoretically pan-caspase inhibition could be an efficient tool to limit apoptosis and thereby the extent of TBI, potential cross-talk between various avenues of CD suggests that more upstream events, particularly the preservation of the cellular energy homeostasis (cyclosporine-A, poly ADP ribose polymerase (PARP) inhibition, hypothermia treatment) may represent more efficient therapeutic targets hopefully also translated to the clinical care of the severely head injured.

Changes of PACAP level in cerebrospinal fluid and plasma of patients with severe traumatic brain injury

PACAP has well-known neuroprotective potential including traumatic brain injury (TBI). Its level is up-regulated following various insults of the CNS in animal models. A few studies have documented alterations of PACAP levels in human serum. The time course of post-ictal PACAP levels, for example, show correlation with migraine severity. Very little is known about the course of PACAP levels following CNS injury in humans and the presence of PACAP has not yet been detected in cerebrospinal fluid (CSF) of subjects with severe TBI (sTBI). The aim of the present study was to determine whether PACAP occurs in the CSF and plasma (Pl) of patients that suffered sTBI and to establish a time course of PACAP levels in the CSF and Pl. Thirty eight subjects with sTBI were enrolled with a Glasgow Coma Scale ≤8 on admission. Samples were taken daily, until the time of death or for maximum 10 days. Our results demonstrated that PACAP was detectable in the CSF, with higher concentrations in patients with TBI. PACAP concentrations markedly increased in both Pl and CSF in the majority of patients 24-48h after the injury stayed high thereafter. In cases of surviving patients, Pl and CSF levels displayed parallel patterns, which may imply the damage of the blood-brain barrier. However, in patients, who died within the first week, Pl levels were markedly higher than CSF levels, possibly indicating the prognostic value of high Pl PACAP levels.

Aquaporin-4 distribution in control and stressed astrocytes in culture and in the cerebrospinal fluid of patients with traumatic brain injuries.

Distribution of aquaporin-4 (AQP4) was studied by western analysis and immunofluorescence in rat astrocytes exposed to either hypothermic (30xa0°C) or hyperosmolar (0.45xa0M sucrose) stress, and in the cerebrospinal fluid (CSF) of patients who suffered traumatic brain injury (TBI). CSF was obtained from 5 healthy subjects and from 20 patients suffering from severe TBI. CSF samples were taken at admission and on days 3 and 5–7. Here we report that, in response to both hypothermia and hyperosmolar stress, AQP4 was markedly reduced in cultured astrocytes. We also found that AQP4 significantly increased in patients with severe brain injury in respect to healthy subjects (Pxa0<xa00.002). AQP4 in CSF remained unchanged in patients with elevated intracranial pressure (ICP), whereas there was a clear tendency to further increase in those patients whose ICP could be controlled within the normal range. We conclude that AQP4 levels in CSF are elevated after TBI and it might serve as a useful biochemical marker to assess brain water metabolism in clinical settings.