Biomarkerek szerepe a koponya/agysérülés súlyosságának, kimenetelének és a therápia hatékonyságának megítélésében = The role of biomarkers in the assessment of injury-severity, outcome and therapeutic efficacy in traumatic brain injury

A kutatás legfőbb eredményei az alábbiak: 1., Elsőként igazoltuk, hogy a súlyos kopnyasérültek liquorában a traumától eltelt idővel összefüggésben intakt spectrin és lebontási termékei szaporodnak fel; ezek megjelenése a koponya sérülésre specifikus jelenségnek tekinthető, ráadásul e lebontási termékek koncentrációja valószínűsíthetően összefüggést mutat a koponyasérülés súlyosságával és a kimenetellel is. E vizsgálatok a Munkacsoport Department of Defense (US) támogatású multicentrikus klinikai tanulmány előkészítésében és kivitelezésében történő részvételét eredményezték. 2., Patkány kísérletes traumás modellben végzett experimentális therápiás vizsgálatok során a diffúz axon károsodás gátlását igazoltuk posttraumás pituitary adenylate cyclase activating peptide adásával impakt akcelerációs és centralis folyadék percussiós modellen. 3., Elsőként írtuk le a különböző súlyosságú koponyasérülés hatására a gerincvelőben létrejövő diffúz axonális károsodás jelenségét. 4. A klinikai adatbázis feldolgozása során a morbiditási-mortalitási esélyeket meghatározó, az intézményi ellátás auditálására is lehetőséget nyújtó, a Marshall score és a Rotterdam score validálásán, továbbfejlesztésén alapuló CT-klasszifikációs rendszert dolgoztunk ki. A három éves kutatómunka során 20 közlemény, könyvfejezet és kongresszusi kivonat született, a peer reviewed közlemények kumulatív impakt faktora 17 feletti. | Major achievements of the project are the following: 1., We have provided the first evidence that traumatic brain injury in human leads to the accumulation of intact spectrin and its? breakdown products and that the appearance of these substances in the cerebrospinal fluid follows a well defined temporal pattern while also associated with injury severity and most probably with outcome, too. 2., Posttraumatic application of pituitary adenylate cyclase activating peptide resulted in the inhibition of diffuse axonal injury both in the impact acceleration- as well as the central fluid percussion model of diffuse traumatic brain injury in rats. 3., These studies provided the first description of diffuse axonal injury in the spinal cord evoked by/associated with diffuse traumatic brain injury of various severity. 4., We have developed a new scoring system based upon the first posttraumatic non-contrast skull CT scan that is capable of predicting outcome and represents an updated version and combination of the Rotterdam-score and the Marshall-classification. This three-years project led to the accumulation of 20 publications of various forms including peer reviewed articles with an impact factor of over 17

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

A Novel PARP Inhibitor L-2286 in a Rat Model of Impact Acceleration Head Injury: An Immunohistochemical and Behavioral Study

We examined the neuro/axono-protective potential of a novel poly (ADP-ribose) polymerase (PARP) inhibitor L-2286 in a rat impact acceleration brain injury model. Male Wistar rats (n = 70) weighing 300–350 grams were used to determine the most effective intracerebroventricular (i.c.v.) dose of L-2286 administered 30 min after injury, and to test the neuroprotective effect at two time points (immediately, and 30 min after injury). The neuroprotective effect of L-2286 was tested using immunohistochemical (amyloid precursor protein and mid-sized mouse anti-neurofilament clone RMO-14.9 antibody) and behavioral tests (beam-balance, open-field and elevated plus maze). At both time-points, a 100 μg/rat dose of i.c.v. L-2286 significantly (p < 0.05) reduced the density of damaged axons in the corticospinal tract and medial longitudinal fascicle compared to controls. In the behavioral tests, treatment 30 min post-injury improved motor function, while the level of anxiety was reduced in both treatment protocols

The predictive value of peri-infarct flow transients in focal brain ischemia

Animal studies havebeen shown that spreading depolarizations(SD)play an importantrolein lesion progression during focal ischemia. Therefore SDs might serve as biomarkers of injury progressin ischemic stroke and in other SD related disordersin order to overcome translational roadblocks. Electrophysiological recordings of SDs havealreadybeenperformedin human studies, where the patient’scondition requirescraniotomy (for example subarachnoidhaemorrhage, malignant middle cerebral artery infarctionandsevere traumatic brain injury).However, anon-invasive, extracranialmonitoring of SDs would allow investigators to enroll a largerpatient population (all the patients with ischemic stroke and minor head trauma) immediately after the injury onset into the studies. The limitationsof extracranial recording of SDs turn the interest intomonitoring alternativebiomarkerssuch as peri-infarct flow transients(PIFTs)whichare the hemodynamical correlatesof SDsin stroke. The aim of this thesis was to investigate if the parameters of the PIFTs (number and the amplitudes) alone or combined with other flow parameters(intra-ischemic flow, level of reperfusion) collected by laser Doppler can predict histological outcomein experimental ischemic stroke.We hypothesizedalso that the amplitude and the morphology of flow transients show regional heterogeneity and therefore it can be helpful in distinguishing the ischemic core, penumbra and peri-ischemic area. We first determined the coupling rate between the DC deflections and PIFTs in amodel of filament occlusion (n=32) andfound that 93 % of the PIFTs recorded by an LD probe are tightlycoupled to DC deflections recordedby epidural silver chloride electrodes. The post hoc analysis of filament occluded animals (n=55) revealed that the combination of intra-ischemic blood flow and the number of PIFTs together is a good, earlypredictor ofhistological outcome. The spatial distribution of the amplitudes and the morphology were analyzed both inthefilament occlusionmodel(n=10)andin thephotochemically induced distal occlusion of the middle cerebral artery(n=8).We found thatlower residual flow, smaller amplitudes anda higher percentage of hypoperfusive flow transients is characteristic for penumbral areas, especiallycloser to the core. Ahigher residual blood flow andamplitude of flow transients along with alarger percentage ofhyperemicand hyperemia dominant biphasicflow transients indicatesperi-ischemic area.We conclude that PIFTs arepotential biomarkersin human studies

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches

PET/MRI in the Presurgical Evaluation of Patients with Epilepsy: A Concordance Analysis

The aim of our prospective study was to evaluate the clinical impact of hybrid [18F]-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging ([18F]-FDG PET/MRI) on the decision workflow of epileptic patients with discordant electroclinical and MRI data. A novel mathematical model was introduced for a clinical concordance calculation supporting the classification of our patients by subgroups of clinical decisions. Fifty-nine epileptic patients with discordant clinical and diagnostic results or MRI negativity were included in this study. The diagnostic value of the PET/MRI was compared to other modalities of presurgical evaluation (e.g., electroclinical data, PET, and MRI). The results of the population-level statistical analysis of the introduced data fusion technique and concordance analysis demonstrated that this model could be the basis for the development of a more accurate clinical decision support parameter in the future. Therefore, making the establishment of “invasive” (operable and implantable) and “not eligible for any further invasive procedures” groups could be much more exact. Our results confirmed the relevance of PET/MRI with the diagnostic algorithm of presurgical evaluation. The introduction of a concordance analysis could be of high importance in clinical and surgical decision-making in the management of epileptic patients. Our study corroborated previous findings regarding the advantages of hybrid PET/MRI technology over MRI and electroclinical data

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

Purpose This 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. Methods We 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 10 years, but recent data on “classical” markers (S-100B, neuron-specific enolase, etc.) were also examined. Results We identified 85 articles focusing on clinical use of biomarkers; 58 articles were prospective cohort studies with injury and/or outcome assessment. Conclusions We 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 welldefined 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