Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n = 22), moderate (moTBI; n = 14) or mild TBI (mTBI; n = 108) according to Glasgow Coma Scale. The control group (n = 28) comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n = 23), moTBI (n = 7), mTBI (n = 37) patients and controls (n = 27). We show that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC = 0.84 in validation cohort). Addition of the metabolites to the established clinical model (CRASH), comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified ‘TBI metabotype’ in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new avenue for the development of diagnostic and prognostic markers of broad spectrum of TBIs.

Plasma metabolomics profiles in rats with acute traumatic brain injury

“…Several metabolomics-based studies of TBI have been published. Orešič M et al reported a comprehensive metabolic profiling of serum samples from TBI patients and the controls in two independent cohorts [ 31 ]. This study showed that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives were strongly associated with the severity of TBI.…”

Medium-chain Fatty Acids as Biomarkers of Mitochondrial Dysfunction in Traumatic Brain Injury

“…In the current issue of EBioMedicine, Orešič et al (2016) describe the application of a metabolomic platform based on bi-dimensional gas chromatography coupled to high-resolution mass spectrometry (GC × GC-TOF-MS) to identify biomarkers in serum samples that could associate with disease severity and predict the outcomes of TBI patients. For this purpose, two independent cohorts were enrolled with the aim to validate results obtained in the discovery phase, comprising mild, moderate and severe TBI patients as well as orthopedic controls.…”

Metabolomics Profiling As a Diagnostic Tool in Severe Traumatic Brain Injury

“…There are three studies that have utilized a lipidomics approach in TBI research: in a murine model ( 60 ) and in humans ( 61 , 62 ), while two studies have employed metabolomics approach in humans with TBI ( 63 , 64 ). Additionally, there are 1 H-NMR metabolomics studies conducted on murine brain tissue specimens and plasma ( 65 ), and on human CSF ( 66 ).…”

“…TBIcare investigators and Turku Centre for Biotechnology Systems Medicine research group applied comprehensive metabolic profiling of serum samples from two large independent cohorts of patients with full spectrum of TBI and orthopedic injuries ( 64 ). Serum metabolomic profiles from 144 patients with mild, moderate or severe TBI were investigated.…”

“… In addition to the above metabolites, four unknown sugar derivatives, a phenolic metabolite and an unknown amino acid form a model that predicts patient outcomes with AUC of 0.84 ( 64 ) . …”