The longitudinal biochemical profiling of TBI in a drop weight model of TBI

Abstract

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, particularly among individuals under the age of 45. It is a complex, and heterogeneous disease with a multifaceted pathophysiology that remains to be elucidated. Metabolomics has the potential to identify metabolic pathways and unique biochemical profiles associated with TBI. Herein, we employed a longitudinal metabolomics approach to study TBI in a weight drop mouse model to reveal metabolic changes associated with TBI pathogenesis, severity, and secondary injury. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, we biochemically profiled post-mortem brain from mice that suffered mild TBI (N = 25; 13 male and 12 female), severe TBI (N = 24; 11 male and 13 female) and sham controls (N = 16; 11 male and 5 female) at baseline, day 1 and day 7 following the injury. 1H NMR-based metabolomics, in combination with bioinformatic analyses, highlights a few significant metabolites associated with TBI severity and perturbed metabolism related to the injury. We report that the concentrations of taurine, creatinine, adenine, dimethylamine, histidine, N-Acetyl aspartate, and glucose 1-phosphate are all associated with TBI severity. Longitudinal metabolic observation of brain tissue revealed that mild TBI and severe TBI lead distinct metabolic profile changes. A multi-class model was able to classify the severity of injury as well as time after TBI with estimated 86% accuracy. Further, we identified a high degree of correlation between respective hemisphere metabolic profiles (r > 0.84, p < 0.05, Pearson correlation). This study highlights the metabolic changes associated with underlying TBI severity and secondary injury. While comprehensive, future studies should investigate whether: (a) the biochemical pathways highlighted here are recapitulated in the brain of TBI sufferers and (b) if the panel of biomarkers are also as effective in less invasively harvested biomatrices, for objective and rapid identification of TBI severity and prognosis.

Metabolome-Wide Mendelian Randomization Assessing the Causal Role of Serum and Cerebrospinal Metabolites in Traumatic Brain Injury

“…Recent advances in serum metabolomic studies have identified several serum biomarkers, such as choline phospholipids, that indicate the risk of secondary injury in the aftermath of TBI [ 10 ]. In a metabolome-wide study, creatinine was reported to be associated with the severity of TBI [ 31 ], and Zheng et al concluded that elevated creatinine levels are related to a higher frequency of regaining consciousness in male patients [ 32 ]. As an efficient scavenger of free radicals, creatinine has demonstrated an antioxidant effect on the brain that decreases oxidative stress in the secondary injury response of TBI [ 33 ].…”

Blood Urea Nitrogen-to-Albumin Ratio May Predict Mortality in Patients with Traumatic Brain Injury from the MIMIC Database: A Retrospective Study

“…It's a global burden, affecting millions and leading to disability, mortality, and significant social and economic costs [2,3]. Although there have been studies on mortality predictive models and predictors in patients with TBI, most of them involved many variables and exhibited high complexity [4][5][6], and few of them found strong and concise predictors for patients with TBI.…”