Assessing Protein Biomarkers to Detect Lethal Acute Traumatic Brain Injuries in Cerebrospinal Fluid

Abstract

Diagnosing traumatic brain injury (TBI) from body fluids in cases where there are no obvious external signs of impact would be useful for emergency physicians and forensic pathologists alike. None of the previous attempts has so far succeeded in establishing a single biomarker to reliably detect TBI with regards to the sensitivity: specificity ratio in a post mortem setting. This study investigated a combination of body fluid biomarkers (obtained post mortem), which may be a step towards increasing the accuracy of biochemical TBI detection. In this study, serum and cerebrospinal fluid (CSF) samples from 30 acute lethal TBI cases and 70 controls without a TBI-related cause of death were evaluated for the following eight TBI-related biomarkers: brain-derived neurotrophic factor (BDNF), ferritin, glial fibrillary acidic protein (GFAP), interleukin 6 (IL-6), lactate dehydrogenase, neutrophil gelatinase-associated lipocalin (NGAL), neuron-specific enolase and S100 calcium-binding protein B. Correlations among the individual TBI biomarkers were assessed, and a specificity-accentuated threshold value analysis was conducted for all biomarkers. Based on these values, a decision tree modelling approach was performed to assess the most accurate biomarker combination to detect acute lethal TBIs. The results showed that 92.45% of acute lethal TBIs were able to be diagnosed using a combination of IL-6 and GFAP in CSF. The probability of detecting an acute lethal TBI was moderately increased by GFAP alone and considerably increased by the remaining biomarkers. BDNF and NGAL were almost perfectly correlated (p = 0.002; R2 = 0.944). This study provides evidence that acute lethal TBIs can be detected to a high degree of statistical accuracy using forensic biochemistry. The high inter-individual correlations of biomarkers may help to estimate the CSF concentration of an unknown biomarker, using extrapolation techniques.

Forensic biomarkers of lethal traumatic brain injury

“…2). Of these, six studies reported results dealing with IL-6 [21][22][23][24][25][26]; five with GFAP [11,13,24,26,27], LDH [23,24,26,28,29], and S100B [7,26,[30][31][32]; four with NSE [24,26,30,31]; three with BDNF [11,24,26], MAPT [13,33,34], and ferritin [23,24,26]; and two with NGAL [11,26]. Information regarding cause of death determination and survival time estimation are presented below.…”

“…CSF concentrations of S100B were significantly higher in TBI fatalities compared to controls (isolated torso trauma, cerebrovascular injury, and sudden natural deaths) [30,31]. Recently, it was stated that a fatal acute TBI (survival time less than 2 h) can be detected with 79% accuracy and 97% specificity in post-mortem CSF when the S100B concentration reaches a threshold of 2267 ng/ml [26]. In serum, S100B was significantly higher in TBI cases compared with Fig.…”

“…When IL-6 levels of TBI fatalities were compared to fatalities that died from isolated torso trauma, CSF but not serum levels were significantly higher [11]. Recently, it was shown that a lethal acute TBI (survival time less than 2 h) can be detected with an accuracy of 86% and a specificity of 96% in post-mortem CSF when the IL-6 concentration reaches a threshold value of 99.1 pg/ml [26]. Trauma fatalities including TBI fatalities revealed significantly higher serum values compared to atraumatic deaths resulting from atraumatic causes of death as well as natural deaths [22].…”

“…CSF NSE values > 6000 ng/ml were exclusively detected in TBI cases with a survival time between 15 min and 5 days [30]. Recently, it was stated that a lethal acute TBI (survival time less than 2 h) can be detected with an accuracy of 83% and a specificity of 97% in post-mortem CSF when the NSE concentration reaches a threshold value of 599 ng/ml [26]. Peak CSF concentrations of NSE were reached within survival times of 3 to 4 days [31].…”

“…When the GFAP CSF level exceeds 385.5 ng/ml, a fatal TBI can be diagnosed with a sensitivity of 71.1% and a specificity of 71.4% [11]. For fatal TBIs with a survival time of fewer than 2 h, a GFAP CSF concentration of 134 ng/ml discriminates a TBI fatality from control fatalities (acute myocardial infarction, diffuse cerebral hypoxia, and isolated torso trauma) with an accuracy of 78% and a specificity of 94% [26]. Contrary to the study of Ondruschka et al [11], another post-mortem study revealed no differences in serum GFAP level between fatalities with macroscopically visible brain damage (including TBI) compared to control fatalities (cardiac cause, respiratory cause, intoxications, exsanguinations, or multiorgan failures) [27].…”