Using metabolomics to predict severe traumatic brain injury outcome (GOSE) at 3 and 12 months (original) (raw)
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Background Prognostication is very important to clinicians and families during the early management of severe traumatic brain injury (sTBI), however, there are no gold standard biomarkers to determine prognosis in sTBI. As has been demonstrated in several diseases, early measurement of serum metabolomic profiles can be used as sensitive and specific biomarkers to predict outcome. Methods We prospectively enrolled adults with sTBI (Glasgow coma scale, GCS ≤ 8) in a multicenter Canadian TBI (CanTBI) study. Serum samples were drawn on the 1st and 4th day following injury for metabolomic profiling. The Glasgow outcome scale extended (GOSE) was collected at 3- and 12-months post-injury. Targeted direct infusion liquid chromatography tandem mass spectrometry (DI/LC-MS/MS) and untargeted proton nuclear magnetic resonance spectroscopy (1H-NMR) were used to profile serum metabolites. Multivariate analysis was used to determine the association between serum metabolomics and GOSE, dichotomized...
Serum metabolome associated with severity of acute traumatic brain injury
Nature Communications
Complex metabolic disruption is a crucial aspect of the pathophysiology of traumatic brain injury (TBI). Associations between this and systemic metabolism and their potential prognostic value are poorly understood. Here, we aimed to describe the serum metabolome (including lipidome) associated with acute TBI within 24 h post-injury, and its relationship to severity of injury and patient outcome. We performed a comprehensive metabolomics study in a cohort of 716 patients with TBI and non-TBI reference patients (orthopedic, internal medicine, and other neurological patients) from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) cohort. We identified panels of metabolites specifically associated with TBI severity and patient outcomes. Choline phospholipids (lysophosphatidylcholines, ether phosphatidylcholines and sphingomyelins) were inversely associated with TBI severity and were among the strongest predictors of TBI patient outcomes...
Metabolomics in severe traumatic brain injury: a scoping review
Research Square (Research Square), 2023
Background: Diagnosis and prognostication of severe traumatic brain injury (sTBI) continue to be problematic despite research efforts for years. There is currently no clinically reliable biomarkers, though advances in protein biomarkers are being made. Utilizing Omics technology, particularly metabolomics, may provide new diagnostic biomarkers for severe traumatic brain injury. Several published studies have attempted to determine speci c metabolites and metabolic pathways involved; these studies will be reviewed. Aims: This scoping review aims to summarize current literature concerning metabolomics in severe traumatic brain injury, review the comprehensive data and identify commonalities, if any, to de ne metabolites with potential clinical use. In addition, we will examine related metabolic pathways through pathway analysis. Methods: Scoping review methodology was used to examine the current literature published in Embase, Scopus, PubMed and Medline. An initial 1090 publications were found and vetted with speci c inclusion/exclusion criteria. 20 publications were selected for further examination and summary. Metabolic data was classi ed using the Human Metabolome Database (HMDB) and arranged to determine the recurrent metabolites and classes found in severe traumatic brain injury. To help understand potential mechanisms of injury, pathway analysis was performed using these metabolites and the Kyoto Encylcopedia of Genes and Genomes (KEGG) Pathway Database. Results: Several metabolites related to severe traumatic brain injury and their effects on biological pathways are identi ed in this review. Proline, citrulline, lactate, alanine, valine, leucine and serine were all decreased in adults post severe traumatic brain injury, whereas both octanoic and decanoic acid were increased post injury. Carboxylic acids tend to decrease following severe traumatic brain injury while hydroxy acids and organooxygen compounds tend to increase. Pathway analysis showed signi cantly affected glycine and serine metabolism, glycolysis, branched chain amino acid (BCAA) metabolism and other amino acid metabolisms. Surprisingly, no tricarboxylic acid cycle metabolites were affected. Conclusion: Aside from select few metabolites, classi cation of a metabolic pro le proved di cult due to signi cant ambiguity between study design, type of sample, sample size, metabolomic detection techniques and other confounding variables. Given the trends found in some studies, further metabolomics investigation of severe traumatic brain injury may be useful to identify clinically relevant metabolites.
Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury
EBioMedicine, 2016
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 metabolomic biomarkers accurately classify acute mild traumatic brain injury from controls
PloS one, 2018
Past and recent attempts at devising objective biomarkers for traumatic brain injury (TBI) in both blood and cerebrospinal fluid have focused on abundance measures of time-dependent proteins. Similar independent determinants would be most welcome in diagnosing the most common form of TBI, mild TBI (mTBI), which remains difficult to define and confirm based solely on clinical criteria. There are currently no consensus diagnostic measures that objectively define individuals as having sustained an acute mTBI. Plasma metabolomic analyses have recently evolved to offer an alternative to proteomic analyses, offering an orthogonal diagnostic measure to what is currently available. The purpose of this study was to determine whether a developed set of metabolomic biomarkers is able to objectively classify college athletes sustaining mTBI from non-injured teammates, within 6 hours of trauma and whether such a biomarker panel could be effectively applied to an independent cohort of TBI and con...
Metabolomics, 2016
We aim to identify candidate brain biomarkers for, and to elucidate the pathophysiology of closed traumatic brain injury (TBI). Nuclear magnetic resonance (NMR) based metabolomic analysis was performed on the whole brain of mice undergoing TBI using a validated technique. There were 10 TBI mice compared to 8 sham operated controls. A total of 45 metabolites were evaluated. There was a statistically significant alteration in concentrations of 29 metabolites in TBI brains as compared to controls (FDR \0.05). Profound disturbances of several metabolic pathways (FDR\1E-07), including pathways associated with purine, alanine, aspartate and glutamine and glutathione metabolism were observed. Also, a significant elevation in glutamate (the main excitatory neurotransmitter) and depression of GABA (the main inhibitory neurotransmitter) was observed. Four metabolites, ADP, AMP, NAD?, and IMP were the most important indicators of TBI, relative to normal controls. All were elevated in the TBI mice. A combination of these 4 biomarkers produced a perfect predictor of TBI status, AUC (95 % CI) = 1.0 (1.0, 1.0). We also detected significant disturbances in mitochondrial function, energy metabolism, neurotransmitter metabolism and other important biochemical pathways in TBI mouse brains. Further studies to assess the utility of metabolomics to detect and classify the severity of and assess the prognosis of TBI is warranted.
Biomedicines
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is frequently found in athletes and those who have experienced repetitive head traumas. CTE is associated with a variety of neuropathologies, which cause cognitive and behavioral impairments in CTE patients. However, currently, CTE can only be diagnosed after death via brain autopsy, and it is challenging to distinguish it from other neurodegenerative diseases with similar clinical features. To better understand this multifaceted disease and identify metabolic differences in the postmortem brain tissues of CTE patients and control subjects, we performed ultra-high performance liquid chromatography–mass spectrometry (UPLC-MS)-based non-targeted metabolomics. Through multivariate and pathway analysis, we found that the brains of CTE patients had significant changes in the metabolites involved in astrocyte activation, phenylalanine, and tyrosine metabolism. The unique metabolic characteristics of CTE identified ...
Metabolomic Analysis of Cerebral Spinal Fluid from Patients with Severe Brain Injury
Brain Edema XV, 2013
Proton nuclear magnetic resonance (H-NMR) spectroscopic analysis of cerebral spinal fl uid provides a quick, non-invasive modality for evaluating the metabolic activity of brain-injured patients. In a prospective study, we compared the CSF of 44 TBI patients and 13 non-injured control subjects. CSF was screened for ten parameters: b-glucose (Glu), lactate (Lac), propylene glycol (PG), glutamine (Gln), alanine (Ala), a-glucose (A-Glu), pyruvate (PYR), creatine (Cr), creatinine (Crt), and acetate (Ace). Using mixed effects measures, we discovered statistically signi fi cant differences between control and trauma concentrations (mM). TBI patients had signi fi cantly higher concentrations of PG, while statistical trends existed for lactate, glutamine, and creatine. TBI patients had a signi fi cantly decreased concentration of total creatinine. There were no signi fi cant differences between TBI patients and non-injured controls regarding bor a-glucose, alanine, pyruvate or acetate. Correlational analysis between metabolites revealed that the strongest signi fi cant correlations in non-injured subjects were between band a-glucose (r = 0.74), creatinine and pyruvate (r = 0.74), alanine and creatine (r = 0.62), and glutamine and a-glucose (r = 0.60). For TBI patients, the strongest signi fi cant correlations were between lactate and a-glucose (r = 0.54), lactate and alanine (r = 0.53), and a-glucose and alanine (r = 0.48). The GLM and multimodel inference indicated that the combined metabolites of PG, glutamine, a-glucose, and creatinine were the strongest predictors for CMRO 2 , ICP, and GOSe. By analyzing the CSF of patients with TBI, our goal was to create a metabolomic fi ngerprint for brain injury.
NMR in Biomedicine, 2005
The effects of traumatic brain injury (TBI) on brain chemistry and metabolism were examined in three groups of rats using high-resolution 1 H NMR metabolomics of brain tissue extracts and plasma. Brain injury in the TBI group (n ¼ 6) was produced by lateral fluid percussion and regional changes in brain metabolites were analyzed at 1 h after injury in hippocampus, cortex and plasma and compared with changes in both a sham-surgery control group (n ¼ 6) and an untreated control group (n ¼ 6). Evidence was found of oxidative stress (e.g. decreases in ascorbate of 16.4% (p < 0.01) and 29.7% (p < 0.05) in cortex and hippocampus, respectively) in TBI rats versus the untreated control group, as well as excitotoxic damage (e.g. decreases in glutamate of 14.7% (p < 0.05) and 12.3% (p < 0.01) in the cortex and hippocampus, respectively), membrane disruption (e.g. decreases in the total level of phosphocholine and glycerophosphocholine of 23.0% (p < 0.01) and 19.0% (p < 0.01) in the cortex and hippocampus, respectively) and neuronal injury (e.g. decreases in Nacetylaspartate of 15.3% (p < 0.01) and 9.7% (p > 0.05) in the cortex and hippocampus, respectively). Significant changes in the overall pattern of NMR-observable metabolites using principal components analysis were also observed in TBI animals. Although TBI clearly had an effect on the metabolic profile found in brain tissue, no clear effects could be discerned in plasma samples. This was at least partly due to large variability in dominant glucose and lactate peaks in plasma. However, disruption of the blood-brain barrier and the subsequent movement of metabolites from brain into blood may have been relatively small and below the detection limits of our analytical procedures. Overall, these data indicate that TBI results in several significant changes in brain metabolism early after trauma and that a metabolomic approach based on 1 H NMR spectroscopy can provide a metabolic profile comprising several metabolite classes and allow for relative quantification of such changes within specific brain regions. The results also provide support for further development and application of metabolomic technologies for studying TBI and for the utilization of multivariate models for classifying the extent of trauma within an individual.
Journal of the American Society for Mass Spectrometry, 2020
Traumatic brain injury (TBI) is a serious public health concern for which sensitive and objective 23 diagnostic methods remain lacking. While advances in neuroimaging have improved diagnostic 24 capabilities, the complementary use of molecular biomarkers can provide clinicians with additional insight into the nature and severity of TBI. In this study, a panel of eight metabolites involved in distinct 26 pathophysiological processes related to concussion was quantified using high-performance liquid 27 chromatography-tandem mass spectrometry (HPLC-MS/MS). Specifically, the newly developed method 28 can simultaneously determine urinary concentrations of glutamic acid, homovanillic acid, 5-29 hydroxyindoleacetic acid, methionine sulfoxide, lactic acid, pyruvic acid, N-acetylaspartic acid, and F 2α-30 isoprostane without intensive sample preparation or preconcentration. The method was systematically 31 validated to assess sensitivity (method detection limits: 1-20 μg/L), accuracy (81-124% spike recoveries 32 in urine), and reproducibility (relative standard deviation: 4-12%). The method was ultimately applied to 33 a small cohort of urine specimens obtained from healthy college student volunteers. The method presented 34 here provides a new technique to facilitate future work aiming to assess the clinical efficacy of these 35 putative biomarkers for noninvasive assessment of TBI.