Using Serum Amino Acids to Predict Traumatic Brain Injury: A Systematic Approach to Utilize Multiple Biomarkers

Abstract

Traumatic brain injury (TBI) can cause biochemical and metabolomic alterations in the brain tissue and serum. These alterations can be used for diagnosis and prognosis of TBI. Here, the serum concentrations of seventeen amino acids (AA) were studied for their potential utility as biomarkers of TBI. Twenty-five female, 4-week-old piglets received diffuse (n = 13) or focal (n = 12) TBI. Blood samples were obtained both pre-injury and at either 24-h or 4-days post-TBI. To find a robust panel of biomarkers, the results of focal and diffuse TBIs were combined and multivariate logistic regression analysis, coupled with the best subset selection technique and repeated k-fold cross-validation method, was used to perform a thorough search of all possible subsets of AAs. The combination of serum glycine, taurine, and ornithine was optimal for TBI diagnosis, with 80% sensitivity and 86% overall prediction rate, and showed excellent TBI diagnostic performance, with 100% sensitivity and 78% overall prediction rate, on a separate validation dataset including four uninjured and five injured animals. We found that combinations of biomarkers outperformed any single biomarker. We propose this 3-AA serum biomarker panel to diagnose mild-to-moderate focal/diffuse TBI. The systematic approaches implemented herein can be used for combining parameters from various TBI assessments to develop/evaluate optimal multi-factorial diagnostic/prognostic TBI metrics.

Repeated Low-Level Blast Exposure Alters Urinary and Serum Metabolites

“…Serum NAA also showed significant changes following blast exposure. As a highly abundant metabolite in brain tissue, decreased levels of NAA have been reported in the brain following blunt-force brain injury using MRS, suggesting potential leakage into the bloodstream [ 39 ]. The increased serum levels observed in the current study provide supporting evidence of NAA leakage into the bloodstream following brain injury.…”

Association of sub-acute changes in plasma amino acid levels with long-term brain pathologies in a rat model of moderate-severe traumatic brain injury

“…Among the specific amino acids undergoing a decline in previous studies were alanine (Deutschman, 1987), arginine (Flakoll et al, 1995Petersen et al, 1996), glutamine (Deutschman, 1987;Flakoll et al, 1995;Petersen et al, 1996;Yi et al, 2016), proline (Flakoll et al, 1995Louin et al, 2007;Zheng et al, 2017), serine (Flakoll et al, 1995;Yi et al, 2016;Hajiaghamemar et al, 2020), taurine (Flakoll et al, 1995;Hajiaghamemar et al, 2020), threonine (Flakoll et al, 1995;Zheng et al, 2017), tryptophan (Flakoll et al, 1995Taraskina et al, 2022), and the branched-chain amino acids (BAA) leucine, isoleucine, and valine (Vuille-Dit-Bille et al, 2012;Jeter et al, 2013). On the other hand, a small number of other studies have also shown a mixed pattern of increased and decreased plasma amino acids, both in human TBI (Deutschman, 1987;Flakoll et al, 1995;Vuille-Dit-Bille et al, 2012) and animal models (Hajiaghamemar et al, 2020). The amino acids most consistently found to be elevated in these studies were the BAAs and phenylalanine (Deutschman, 1987;Flakoll et al, 1995), which is consistent with our present results.…”

“…There have been conflicting results from previous studies on this topic; some studies reported subacute "nitrogen loss" (Flakoll et al, 1995), namely a general decrease in the plasma levels of the majority of the amino acids in humans (Flakoll et al, 1995;Petersen et al, 1996;Yi et al, 2016) and in animal models of TBI (Louin et al, 2007;Zheng et al, 2017;Taraskina et al, 2022). Among the specific amino acids undergoing a decline in previous studies were alanine (Deutschman, 1987), arginine (Flakoll et al, 1995Petersen et al, 1996), glutamine (Deutschman, 1987;Flakoll et al, 1995;Petersen et al, 1996;Yi et al, 2016), proline (Flakoll et al, 1995Louin et al, 2007;Zheng et al, 2017), serine (Flakoll et al, 1995;Yi et al, 2016;Hajiaghamemar et al, 2020), taurine (Flakoll et al, 1995;Hajiaghamemar et al, 2020), threonine (Flakoll et al, 1995;Zheng et al, 2017), tryptophan (Flakoll et al, 1995Taraskina et al, 2022), and the branched-chain amino acids (BAA) leucine, isoleucine, and valine (Vuille-Dit-Bille et al, 2012;Jeter et al, 2013). On the other hand, a small number of other studies have also shown a mixed pattern of increased and decreased plasma amino acids, both in human TBI (Deutschman, 1987;Flakoll et al, 1995;Vuille-Dit-Bille et al, 2012) and animal models (Hajiaghamemar et al, 2020).…”

“…Indeed, several prior studies have examined changes in plasma or serum amino acid levels after TBI in humans (Deutschman, 1987;Flakoll et al, 1995;Petersen et al, 1996;Vuille-Dit-Bille et al, 2012;Jeter et al, 2013) and in animal models (Louin et al, 2007;Zheng et al, 2017;Taraskina et al, 2022). In a piglet TBI model, plasma levels of glycine, ornithine, and the nonproteinogenic amino acid taurine at 24 h post-injury correlated with central injury in a regression model (Hajiaghamemar et al, 2020).…”

Progress Toward a Multiomic Understanding of Traumatic Brain Injury: A Review

“…Metabolomic biomarkers are currently being widely explored for TBI. 89,[98][99][100][101][102][103][104][105][106][107] Because no single metabolite has yet been identified with sufficient diagnostic power, most reports focus on metabolite panels that explain a significant amount of the variance observed between TBI patients/models (typically controlled cortical impact, fluid percussion, and weight-drop models) and controls (typically healthy individuals or "sham" craniotomy models). 108 A selection of metabolites reported with altered levels in TBI is shown in Table 1.…”