Magnitude Of Brain Injury Research Articles

Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators

BackgroundSeveral biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. MethodsProspective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys® electrochemiluminescence immunoassays on a Cobas e601 instrument. ResultsStatistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0–3 vs. 4–6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95–100% specificities. ConclusionsThis prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.

Long-term changes in metabolic brain network drive memory impairments in rats following neonatal hypoxia-ischemia.

Hypoxia and cerebral ischemia (HI) events are capable of triggering important changes in brain metabolism, including glucose metabolism abnormalities, which may be related to the severity of the insult. Using positron emission microtomography (microPET) with [18F]fluorodeoxyglucose (18F-FDG), this study proposes to assess abnormalities of brain glucose metabolism in adult rats previously submitted to the neonatal HI model. We hypothesize that cerebral metabolic outcomes will be associated with cognitive deficits and magnitude of brain injury. Seven-day-old rats were subjected to an HI model, induced by permanent occlusion of the right common carotid artery and systemic hypoxia. 18F-FDG-microPET was used to assess regional and whole brain glucose metabolism in rats at 60 postnatal days (PND 60). An interregional cross-correlation matrix was utilized to construct metabolic brain networks (MBN). Rats were also subjected to the Morris Water Maze (MWM) to evaluate spatial memory and their brains were processed for volumetric evaluation. Brain glucose metabolism changes were observed in adult rats after neonatal HI insult, limited to the right brain hemisphere. However, not all HI animals exhibited significant cerebral hypometabolism. Hippocampal glucose metabolism was used to stratify HI animals into HI hypometabolic (HI-h) and HI non-hypometabolic (HI non-h) groups. The HI-h group had drastic MBN disturbance, cognitive deficit, and brain tissue loss, concomitantly. Conversely, HI non-h rats had normal brain glucose metabolism and brain tissue preserved, but also presented MBN changes and spatial memory impairment. Furthermore, data showed that brain glucose metabolism correlated with cognitive deficits and brain volume outcomes. Our findings demonstrated that long-term changes in MBN drive memory impairments in adult rats subjected to neonatal hypoxic ischemia, using in vivo imaging microPET-FDG. The MBN analyses identified glucose metabolism abnormalities in HI non-h animals, which were not detected by conventional 18F-FDG standardized uptake value (SUVr) measurements. These animals exhibited a metabolic brain signature that may explain the cognitive deficit even with no identifiable brain damage.

Early serum biomarkers as predictors of brain injury on MRI in neonates with hypoxic-ischemic encephalopathy

Background - Hypoxic-ischemic encephalopathy (HIE) continues to represent a significant burden of neonatal morbidity and mortality worldwide. Therapeutic hypothermia improves the neurodevelopmental outcome in 1 out of 8 infants when initiated within 6 hours of life. However, the clinician lacks an objective algorithm for predicting the severity of brain injury. We hypothesized that the concentrations of two neonatal brain injury biomarkers, Ubiquitin C-terminal hydrolase L1 (UCH-L1) and Glial fibrillary acidic protein (GFAP), will predict the subjective magnitude of brain injury and the volume of injury in the cortex, deep grey matter …

Neuron-Specific Enolase, but Not S100B or Myelin Basic Protein, Increases in Peripheral Blood Corresponding to Lesion Volume after Cortical Impact in Piglets

A peripheral indicator of the presence and magnitude of brain injury has been a sought-after tool by clinicians. We measured neuron-specific enolase (NSE), myelin basic protein (MBP), and S100B, prior to and after scaled cortical impact in immature pigs, to determine if these purported markers increase after injury, correlate with the resulting lesion volume, and if these relationships vary with maturation. Scaled cortical impact resulted in increased lesion volume with increasing age. Concentrations of NSE, but not S100B or MBP, increased after injury in all age groups. The high variability of S100B concentrations prior to injury may have precluded detection of an increase due to injury. Total serum markers were estimated, accounting for the allometric growth of blood volume, and resulted in a positive correlation of both NSE and S100B with lesion volume. Even with allometric scaling of blood volume and a uniform mechanism of injury, NSE had only a fair to poor predictive value. In a clinical setting, where the types of injuries are varied, more investigation is required to yield a panel of serum markers that can reliably predict the extent of injury. Allometric scaling may improve estimation of serum marker release in pediatric populations.

Hypothermia and Other Treatment Options for Neonatal Encephalopathy: An Executive Summary of the Eunice Kennedy Shriver NICHD Workshop

HIE is not a single disease from a single cause, and is characterized by great diversity in the timing and magnitude of brain injury. It is therefore unreasonable to expect any single intervention to provide uniformly favorable outcome. The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all infants with HIE undergoing any treatment. In spite of rapidly accumulating clinical and laboratory data related to hypothermia as a neuroprotective strategy for HIE, the speakers and discussants at the workshop underscored numerous gaps in knowledge in this field summarized in the Table, which compares the gaps identified at the 2005 NICHD workshop8 with current gaps. The participants noted that with only six completed studies1-6 providing information on follow-up for up to 18 months of age, the longer-term neurodevelopmental impact of hypothermia for HIE are pending.23,24 This, they concluded, should lead to an overall measure of caution in applying the new therapy of hypothermia indiscriminately for all cases of HIE. Table 1 Comparison of Categories of Gaps in Knowledge and Change from 2005 to 2010 Based on the available data and large knowledge gaps, the expert panel suggested that although hypothermia is unequivocally a promising therapy for HIE, a substantial proportion of infants still suffer from death or disability despite treatment. Further analysis of existing trial data, development of adjuvant therapies to hypothermia, development of biomarkers and further refinements of hypothermia therapy for use in infants suffering from HIE and clinical trials of therapeutic hypothermia in mid resource settings with different risk factors but adequate facilities and infrastructure are all urgently needed and were identified as areas of high priority for study.