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Oft HC, Simon DW, Sun D. New insights into metabolism dysregulation after TBI. J Neuroinflammation 2024; 21:184. [PMID: 39075578 PMCID: PMC11288120 DOI: 10.1186/s12974-024-03177-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 07/16/2024] [Indexed: 07/31/2024] Open
Abstract
Traumatic brain injury (TBI) remains a leading cause of death and disability that places a great physical, social, and financial burden on individuals and the health system. In this review, we summarize new research into the metabolic changes described in clinical TBI trials, some of which have already shown promise for informing injury classification and staging. We focus our discussion on derangements in glucose metabolism, cell respiration/mitochondrial function and changes to ketone and lipid metabolism/oxidation to emphasize potentially novel biomarkers for clinical outcome prediction and intervention and offer new insights into possible underlying mechanisms from preclinical research of TBI pathology. Finally, we discuss nutrition supplementation studies that aim to harness the gut/microbiome-brain connection and manipulate systemic/cellular metabolism to improve post-TBI recovery. Taken together, this narrative review summarizes published TBI-associated changes in glucose and lipid metabolism, highlighting potential metabolite biomarkers for clinical use, the cellular processes linking these markers to TBI pathology as well as the limitations and future considerations for TBI "omics" work.
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Affiliation(s)
- Helena C Oft
- Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15213, USA
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Dennis W Simon
- Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Dandan Sun
- Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15213, USA.
- Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
- Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15213, USA.
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Pulliam A, Gier EC, Gaul DA, Moore SG, Fernández FM, LaPlaca MC. Comparing Brain and Blood Lipidome Changes following Single and Repetitive Mild Traumatic Brain Injury in Rats. ACS Chem Neurosci 2024; 15:300-314. [PMID: 38179922 PMCID: PMC10797623 DOI: 10.1021/acschemneuro.3c00603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 12/07/2023] [Accepted: 12/07/2023] [Indexed: 01/06/2024] Open
Abstract
Traumatic brain injury (TBI) is a major health concern in the United States and globally, contributing to disability and long-term neurological problems. Lipid dysregulation after TBI is underexplored, and a better understanding of lipid turnover and degradation could point to novel biomarker candidates and therapeutic targets. Here, we investigated overlapping lipidome changes in the brain and blood using a data-driven discovery approach to understand lipid alterations in the brain and serum compartments acutely following mild TBI (mTBI) and the potential efflux of brain lipids to peripheral blood. The cortices and sera from male and female Sprague-Dawley rats were analyzed via ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) in both positive and negative ion modes following single and repetitive closed head impacts. The overlapping lipids in the data sets were identified with an in-house data dictionary for investigating lipid class changes. MS-based lipid profiling revealed overall increased changes in the serum compartment, while the brain lipids primarily showed decreased changes. Interestingly, there were prominent alterations in the sphingolipid class in the brain and blood compartments after single and repetitive injury, which may suggest efflux of brain sphingolipids into the blood after TBI. Genetic algorithms were used for predictive panel selection to classify injured and control samples with high sensitivity and specificity. These overlapping lipid panels primarily mapped to the glycerophospholipid metabolism pathway with Benjamini-Hochberg adjusted q-values less than 0.05. Collectively, these results detail overlapping lipidome changes following mTBI in the brain and blood compartments, increasing our understanding of TBI-related lipid dysregulation while identifying novel biomarker candidates.
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Affiliation(s)
- Alexis
N. Pulliam
- Coulter
Department of Biomedical Engineering, Georgia
Institute of Technology/Emory University, Atlanta, GA 30332 USA
- Petit
Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Eric C. Gier
- School
of Chemistry and Biochemistry, Georgia Institute
of Technology, Atlanta, GA 30332 USA
- Petit
Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - David A. Gaul
- School
of Chemistry and Biochemistry, Georgia Institute
of Technology, Atlanta, GA 30332 USA
- Petit
Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Samuel G. Moore
- School
of Chemistry and Biochemistry, Georgia Institute
of Technology, Atlanta, GA 30332 USA
- Petit
Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Facundo M. Fernández
- School
of Chemistry and Biochemistry, Georgia Institute
of Technology, Atlanta, GA 30332 USA
- Petit
Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Michelle C. LaPlaca
- Coulter
Department of Biomedical Engineering, Georgia
Institute of Technology/Emory University, Atlanta, GA 30332 USA
- Petit
Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
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Gusdon AM, Savarraj JPJ, Redell JB, Paz A, Hinds S, Burkett A, Torres G, Ren X, Badjatia N, Hergenroeder GW, Moore AN, Choi HA, Dash PK. Lysophospholipids Are Associated With Outcomes in Hospitalized Patients With Mild Traumatic Brain Injury. J Neurotrauma 2024; 41:59-72. [PMID: 37551969 PMCID: PMC11071087 DOI: 10.1089/neu.2023.0046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/09/2023] Open
Abstract
Mild traumatic brain injury (mTBI) accounts for 70-90% of all TBI cases. Lipid metabolites have important roles in plasma membrane biogenesis, function, and cell signaling. As TBI can compromise plasma membrane integrity and alter brain cell function, we sought to identify circulating phospholipid alterations after mTBI, and determine if these changes were associated with clinical outcomes. Patients with mTBI (Glasgow Coma Score [GCS] ≥13 and loss of consciousness <30 min) were recruited. A total of 84 mTBI subjects were enrolled after admission to a level I trauma center, with the majority having evidence of traumatic intracranial hemorrhage on brain computed tomography (CT). Plasma samples were collected within 24 h of injury with 32 mTBI subjects returning at 3 months after injury for a second plasma sample to be collected. Thirty-five healthy volunteers were enrolled as controls and had a one-time blood draw. Lipid metabolomics was performed on plasma samples from each subject. Fold change of selected lipid metabolites was determined. Multivariable regression models were created to test associations between lipid metabolites and discharge and 6-month Glasgow Outcomes Scale-Extended (GOSE) outcomes (dichotomized between "good" [GOSE ≥7] and "bad" [GOSE ≤6] functional outcomes). Plasma levels of 31 lipid metabolites were significantly associated with discharge GOSE using univariate models; three of these metabolites were significantly increased, while 14 were significantly decreased in subjects with good outcomes compared with subjects with poor outcomes. In multivariable logistic regression models, higher circulating levels of the lysophospholipids (LPL) 1-linoleoyl-glycerophosphocholine (GPC) (18:2), 1-linoleoyl-GPE (18:2), and 1-linolenoyl-GPC (18:3) were associated with both good discharge GOSE (odds ratio [OR] 12.2 [95% CI 3.35, 58.3], p = 5.23 × 10-4; OR 9.43 [95% CI 2.87, 39.6], p = 7.26 × 10-4; and OR 5.26 [95% CI 1.99, 16.7], p = 2.04 × 10-3, respectively) and 6-month (OR 4.67 [95% CI 1.49, 17.7], p = 0.013; OR 2.93 [95% CI 1.11, 8.87], p = 0.039; and OR 2.57 [95% CI 1.08, 7.11], p = 0.046, respectively). Compared with healthy volunteers, circulating levels of these three LPLs were decreased early after injury and had normalized by 3 months after injury. Logistic regression models to predict functional outcomes were created by adding each of the described three LPLs to a baseline model that included age and sex. Including 1-linoleoyl-GPC (18:2) (8.20% improvement, p = 0.009), 1-linoleoyl-GPE (18:2) (8.85% improvement, p = 0.021), or 1-linolenoyl-GPC (18:3) (7.68% improvement, p = 0.012), significantly improved the area under the curve (AUC) for predicting discharge outcomes compared with the baseline model. Models including 1-linoleoyl-GPC (18:2) significantly improved AUC for predicting 6-month outcomes (9.35% improvement, p = 0.034). Models including principal components derived from 25 LPLs significantly improved AUC for prediction of 6-month outcomes (16.0% improvement, p = 0.020). Our results demonstrate that higher plasma levels of LPLs (1-linoleoyl-GPC, 1-linoleoyl-GPE, and 1-linolenoyl-GPC) after mTBI are associated with better functional outcomes at discharge and 6 months after injury. This class of phospholipids may represent a potential therapeutic target.
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Affiliation(s)
- Aaron M. Gusdon
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Jude PJ Savarraj
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - John B. Redell
- Department of Neurobiology and Anatomy, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Atzhiry Paz
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Sarah Hinds
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Angela Burkett
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Glenda Torres
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Xuefang Ren
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Neeraj Badjatia
- Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Georgene W. Hergenroeder
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Anthony N. Moore
- Department of Neurobiology and Anatomy, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - H. Alex Choi
- Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
| | - Pramod K. Dash
- Department of Neurobiology and Anatomy, McGovern School of Medicine, University of Texas Health Science Center, Houston, Texas, USA
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Nkiliza A, Huguenard CJ, Aldrich GJ, Ferguson S, Cseresznye A, Darcey T, Evans JE, Dretsch M, Mullan M, Crawford F, Abdullah L. Levels of Arachidonic Acid-Derived Oxylipins and Anandamide Are Elevated Among Military APOE ɛ4 Carriers With a History of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder Symptoms. Neurotrauma Rep 2023; 4:643-654. [PMID: 37786567 PMCID: PMC10541938 DOI: 10.1089/neur.2023.0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023] Open
Abstract
Currently approved blood biomarkers detect intracranial lesions in adult patients with mild to moderate traumatic brain injury (TBI) acutely post-injury. However, blood biomarkers are still needed to help with a differential diagnosis of mild TBI (mTBI) and post-traumatic stress disorder (PTSD) at chronic post-injury time points. Owing to the association between phospholipid (PL) dysfunction and chronic consequences of TBI, we hypothesized that examining bioactive PL metabolites (oxylipins and ethanolamides) would help identify long-term lipid changes associated with mTBI and PTSD. Lipid extracts of plasma from active-duty soldiers deployed to the Iraq/Afghanistan wars (control = 52, mTBI = 21, PTSD = 34, and TBI + PTSD = 13) were subjected to liquid chromatography/mass spectrometry analysis to examine oxylipins and ethanolamides. Linear regression analyses followed by post hoc comparisons were performed to assess the association of these lipids with diagnostic classifications. Significant differences were found in oxylipins derived from arachidonic acid (AA) between controls and mTBI, PTSD, and mTBI + PTSD groups. Levels of AA-derived oxylipins through the cytochrome P450 pathways and anandamide were significantly elevated among mTBI + PTSD patients who were carriers of the apolipoprotein E E4 allele. These studies demonstrate that AA-derived oxylipins and anandamide may be unique blood biomarkers of PTSD and mTBI + PTSD. Further, these AA metabolites may be indicative of an underlying inflammatory process that warrants further investigation. Future validation studies in larger cohorts are required to determine a potential application of this approach in providing a differential diagnosis of mTBI and PTSD in a clinical setting.
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Affiliation(s)
- Aurore Nkiliza
- Roskamp Institute, Sarasota, Florida, USA
- James A. Haley VA Hospital, Tampa, Florida, USA
| | - Claire J.C. Huguenard
- Roskamp Institute, Sarasota, Florida, USA
- Open University, Milton Keynes, United Kingdom
| | | | - Scott Ferguson
- Roskamp Institute, Sarasota, Florida, USA
- Open University, Milton Keynes, United Kingdom
| | | | | | | | - Michael Dretsch
- U.S. Army Medical Research Directorate-West, Walter Reed Army Institute of Research, Joint Base Lewis-McChord, Washington, USA
- U.S. Army Aeromedical Research Laboratory, Fort Novosel, Alabama, USA
| | - Michael Mullan
- Roskamp Institute, Sarasota, Florida, USA
- James A. Haley VA Hospital, Tampa, Florida, USA
| | - Fiona Crawford
- Roskamp Institute, Sarasota, Florida, USA
- Open University, Milton Keynes, United Kingdom
- James A. Haley VA Hospital, Tampa, Florida, USA
| | - Laila Abdullah
- Roskamp Institute, Sarasota, Florida, USA
- Open University, Milton Keynes, United Kingdom
- James A. Haley VA Hospital, Tampa, Florida, USA
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Arun P, Wilder DM, Morris AJ, Sabbadini R, Long JB. Cerebrospinal Fluid Levels of Lysophosphatidic Acids Can Provide Suitable Biomarkers of Blast-Induced Traumatic Brain Injury. J Neurotrauma 2023; 40:2289-2296. [PMID: 37279302 DOI: 10.1089/neu.2023.0087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023] Open
Abstract
Blast-induced traumatic brain injury (bTBI) has been identified as the signature injury of Operation Iraqi Freedom and Operation Enduring Freedom. Although the incidence of bTBI increased significantly after the introduction of improvised explosive devices, the mechanism of the injury is still uncertain, which is negatively impacting the development of suitable countermeasures. Identification of suitable biomarkers that could aid in the proper diagnosis of and prognosis for both acute and chronic bTBI is essential since bTBI frequently is occult and may not be associated with overtly detectable injuries to the head. Lysophosphatidic acid (LPA) is a bioactive phospholipid generated by activated platelets, astrocytes, choroidal plexus cells and microglia and is reported to play major roles in stimulating inflammatory processes. The levels of LPA in the cerebrospinal fluid (CSF) have been reported to increase acutely after non-blast related brain injuries. In the present study, we have evaluated the utility of LPA levels measured in the CSF and plasma of laboratory rats as an acute and chronic biomarker of brain injury resulting from single and tightly coupled repeated blast overpressure exposures. In the CSF, many LPA species increased at acute time-points, returned to normal levels at 1 month, and increased again at 6 months and 1 year post-blast overpressure exposures. In the plasma, several LPA species increased acutely, returned to normal levels by 24 h, and were significantly decreased at 1 year post-blast overpressure exposures. These decreases in LPA species in the plasma were associated with decreased levels of lysophosphatidyl choline, suggesting a defective upstream biosynthetic pathway of LPAs in the plasma. Notably, the changes in LPA levels in the CSF (but not plasma) negatively correlated with neurobehavioral functions in these rats, suggesting that CSF levels of LPAs may provide a suitable biomarker of bTBI that reflects severity of injury.
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Affiliation(s)
- Peethambaran Arun
- Blast-Induced Neurotrauma Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Donna M Wilder
- Blast-Induced Neurotrauma Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Andrew J Morris
- Central Arkansas Veterans Affairs Healthcare System, Little Rock, Arkansas, USA
| | - Roger Sabbadini
- Department of Biology, San Diego State University, San Diego, California, USA
| | - Joseph B Long
- Blast-Induced Neurotrauma Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
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Allen J, Pham L, Bond ST, O’Brien WT, Spitz G, Shultz SR, Drew BG, Wright DK, McDonald SJ. Acute effects of single and repeated mild traumatic brain injury on levels of neurometabolites, lipids, and mitochondrial function in male rats. Front Mol Neurosci 2023; 16:1208697. [PMID: 37456524 PMCID: PMC10338885 DOI: 10.3389/fnmol.2023.1208697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 06/16/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Mild traumatic brain injuries (mTBIs) are the most common form of acquired brain injury. Symptoms of mTBI are thought to be associated with a neuropathological cascade, potentially involving the dysregulation of neurometabolites, lipids, and mitochondrial bioenergetics. Such alterations may play a role in the period of enhanced vulnerability that occurs after mTBI, such that a second mTBI will exacerbate neuropathology. However, it is unclear whether mTBI-induced alterations in neurometabolites and lipids that are involved in energy metabolism and other important cellular functions are exacerbated by repeat mTBI, and if such alterations are associated with mitochondrial dysfunction. Methods In this experiment, using a well-established awake-closed head injury (ACHI) paradigm to model mTBI, male rats were subjected to a single injury, or five injuries delivered 1 day apart, and injuries were confirmed with a beam-walk task and a video observation protocol. Abundance of several neurometabolites was evaluated 24 h post-final injury in the ipsilateral and contralateral hippocampus using in vivo proton magnetic resonance spectroscopy (1H-MRS), and mitochondrial bioenergetics were evaluated 30 h post-final injury, or at 24 h in place of 1H-MRS, in the rostral half of the ipsilateral hippocampus. Lipidomic evaluations were conducted in the ipsilateral hippocampus and cortex. Results We found that behavioral deficits in the beam task persisted 1- and 4 h after the final injury in rats that received repetitive mTBIs, and this was paralleled by an increase and decrease in hippocampal glutamine and glucose, respectively, whereas a single mTBI had no effect on sensorimotor and metabolic measurements. No group differences were observed in lipid levels and mitochondrial bioenergetics in the hippocampus, although some lipids were altered in the cortex after repeated mTBI. Discussion The decrease in performance in sensorimotor tests and the presence of more neurometabolic and lipidomic abnormalities, after repeated but not singular mTBI, indicates that multiple concussions in short succession can have cumulative effects. Further preclinical research efforts are required to understand the underlying mechanisms that drive these alterations to establish biomarkers and inform treatment strategies to improve patient outcomes.
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Affiliation(s)
- Josh Allen
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Louise Pham
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Simon T. Bond
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Baker Heart & Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia
| | - William T. O’Brien
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Gershon Spitz
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Monash-Epworth Rehabilitation Research Centre, Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Melbourne, VIC, Australia
| | - Sandy R. Shultz
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Health Sciences, Vancouver Island University, Nanaimo, BC, Canada
- Department of Medicine, University of Melbourne, Parkville, VIC, Australia
| | - Brian G. Drew
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Baker Heart & Diabetes Institute, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia
| | - David K. Wright
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Stuart J. McDonald
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia
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Plasma Lipid Profiles Change with Increasing Numbers of Mild Traumatic Brain Injuries in Rats. Metabolites 2022; 12:metabo12040322. [PMID: 35448509 PMCID: PMC9025508 DOI: 10.3390/metabo12040322] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/23/2022] [Accepted: 03/23/2022] [Indexed: 11/16/2022] Open
Abstract
Mild traumatic brain injury (mTBI) causes structural, cellular and biochemical alterations which are difficult to detect in the brain and may persist chronically following single or repeated injury. Lipids are abundant in the brain and readily cross the blood-brain barrier, suggesting that lipidomic analysis of blood samples may provide valuable insight into the neuropathological state. This study used liquid chromatography-mass spectrometry (LC-MS) to examine plasma lipid concentrations at 11 days following sham (no injury), one (1×) or two (2×) mTBI in rats. Eighteen lipid species were identified that distinguished between sham, 1× and 2× mTBI. Three distinct patterns were found: (1) lipids that were altered significantly in concentration after either 1× or 2× F mTBI: cholesterol ester CE (14:0) (increased), phosphoserine PS (14:0/18:2) and hexosylceramide HCER (d18:0/26:0) (decreased), phosphoinositol PI(16:0/18:2) (increased with 1×, decreased with 2× mTBI); (2) lipids that were altered in response to 1× mTBI only: free fatty acid FFA (18:3 and 20:3) (increased); (3) lipids that were altered in response to 2× mTBI only: HCER (22:0), phosphoethanolamine PE (P-18:1/20:4 and P-18:0/20:1) (increased), lysophosphatidylethanolamine LPE (20:1), phosphocholine PC (20:0/22:4), PI (18:1/18:2 and 20:0/18:2) (decreased). These findings suggest that increasing numbers of mTBI induce a range of changes dependent upon the lipid species, which likely reflect a balance of damage and reparative responses.
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Morel Y, Hegdekar N, Sarkar C, Lipinski MM, Kane MA, Jones JW. Structure-specific, accurate quantitation of plasmalogen glycerophosphoethanolamine. Anal Chim Acta 2021; 1186:339088. [PMID: 34756256 PMCID: PMC8581249 DOI: 10.1016/j.aca.2021.339088] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 09/08/2021] [Accepted: 09/19/2021] [Indexed: 11/16/2022]
Abstract
Changes in plasmalogen glycerophosphoethanolamine (PE-P) composition (structure and abundance) are a key indicator of altered lipid metabolism. Differential changes in the levels of PE-P have been reported in different disease states, including neurodegenerative diseases. Of particular interest, traumatic brain injury (TBI) has resulted in altered expression of glycerophospholipid profiles, including PE-P. To date, most analytical assays assessing PE-P have focused on general lipidomic workflows to evaluate the relative, semi-quantitative abundance of PE-P during disease progression. This approach provides a broad evaluation of PE-P, yet often lacks specificity and sensitivity for individual PE-P structures which is a necessity for robust quantitative data. The present study highlights the development of a targeted, quantitative method using a HILIC separation and selective reaction monitoring mass spectrometry for the confident identification and accurate quantitation of PE-P. Our innovative method incorporates both the sn-1 alkyl vinyl ether and sn-2 acyl chain as product ion transitions, for specific and sensitive quantitation of 100 PE-P structures. Our method also uniquely allowed for the unambiguous assignment and quantitation of di-unsaturated sn-1 PE-P structures, which to date have not been conclusively quantified. Application of this assay to a TBI mouse model resulted in distinct temporal profiles for plasma PE-P up to 28 days post injury. Plasma PE-P were significantly increased 24 h after induced TBI, followed by a gradual reduction to sham concentrations by day 28. Overall, we established a structure-specific, quantitative assay for identification and quantitation of a comprehensive set of PE-P structures with demonstrated relevance to brain injury.
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Affiliation(s)
- Yulemni Morel
- Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, 21201, USA
| | - Nivedita Hegdekar
- Department of Anesthesiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Chinmoy Sarkar
- Department of Anesthesiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
| | - Marta M Lipinski
- Department of Anesthesiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; Department of Anatomy and Neurobiology, University of Maryland, School of Medicine, Baltimore, MD, 21201, USA
| | - Maureen A Kane
- Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, 21201, USA
| | - Jace W Jones
- Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, 21201, USA.
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9
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Javaid S, Farooq T, Rehman Z, Afzal A, Ashraf W, Rasool MF, Alqahtani F, Alsanea S, Alasmari F, Alanazi MM, Alharbi M, Imran I. Dynamics of Choline-Containing Phospholipids in Traumatic Brain Injury and Associated Comorbidities. Int J Mol Sci 2021; 22:ijms222111313. [PMID: 34768742 PMCID: PMC8583393 DOI: 10.3390/ijms222111313] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/12/2021] [Accepted: 10/15/2021] [Indexed: 01/01/2023] Open
Abstract
The incidences of traumatic brain injuries (TBIs) are increasing globally because of expanding population and increased dependencies on motorized vehicles and machines. This has resulted in increased socio-economic burden on the healthcare system, as TBIs are often associated with mental and physical morbidities with lifelong dependencies, and have severely limited therapeutic options. There is an emerging need to identify the molecular mechanisms orchestrating these injuries to life-long neurodegenerative disease and a therapeutic strategy to counter them. This review highlights the dynamics and role of choline-containing phospholipids during TBIs and how they can be used to evaluate the severity of injuries and later targeted to mitigate neuro-degradation, based on clinical and preclinical studies. Choline-based phospholipids are involved in maintaining the structural integrity of the neuronal/glial cell membranes and are simultaneously the essential component of various biochemical pathways, such as cholinergic neuronal transmission in the brain. Choline or its metabolite levels increase during acute and chronic phases of TBI because of excitotoxicity, ischemia and oxidative stress; this can serve as useful biomarker to predict the severity and prognosis of TBIs. Moreover, the effect of choline-replenishing agents as a post-TBI management strategy has been reviewed in clinical and preclinical studies. Overall, this review determines the theranostic potential of choline phospholipids and provides new insights in the management of TBI.
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Affiliation(s)
- Sana Javaid
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (S.J.); (T.F.); (Z.R.); (A.A.); (W.A.); (I.I.)
- Department of Pharmacy, The Women University, Multan 60000, Pakistan
| | - Talha Farooq
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (S.J.); (T.F.); (Z.R.); (A.A.); (W.A.); (I.I.)
| | - Zohabia Rehman
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (S.J.); (T.F.); (Z.R.); (A.A.); (W.A.); (I.I.)
| | - Ammara Afzal
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (S.J.); (T.F.); (Z.R.); (A.A.); (W.A.); (I.I.)
| | - Waseem Ashraf
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (S.J.); (T.F.); (Z.R.); (A.A.); (W.A.); (I.I.)
| | - Muhammad Fawad Rasool
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan;
| | - Faleh Alqahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (F.A.); (M.M.A.); (M.A.)
- Correspondence: ; Tel.: +966-114697749
| | - Sary Alsanea
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (F.A.); (M.M.A.); (M.A.)
| | - Fawaz Alasmari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (F.A.); (M.M.A.); (M.A.)
| | - Mohammed Mufadhe Alanazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (F.A.); (M.M.A.); (M.A.)
| | - Metab Alharbi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (S.A.); (F.A.); (M.M.A.); (M.A.)
| | - Imran Imran
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; (S.J.); (T.F.); (Z.R.); (A.A.); (W.A.); (I.I.)
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10
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Nessel I, Michael-Titus AT. Lipid profiling of brain tissue and blood after traumatic brain injury. Semin Cell Dev Biol 2021; 112:145-156. [DOI: 10.1016/j.semcdb.2020.08.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/06/2020] [Accepted: 08/08/2020] [Indexed: 11/15/2022]
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11
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Keating CE, Cullen DK. Mechanosensation in traumatic brain injury. Neurobiol Dis 2020; 148:105210. [PMID: 33259894 DOI: 10.1016/j.nbd.2020.105210] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/10/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Traumatic brain injury (TBI) is distinct from other neurological disorders because it is induced by a discrete event that applies extreme mechanical forces to the brain. This review describes how the brain senses, integrates, and responds to forces under both normal conditions and during injury. The response to forces is influenced by the unique mechanical properties of brain tissue, which differ by region, cell type, and sub-cellular structure. Elements such as the extracellular matrix, plasma membrane, transmembrane receptors, and cytoskeleton influence its properties. These same components also act as force-sensors, allowing neurons and glia to respond to their physical environment and maintain homeostasis. However, when applied forces become too large, as in TBI, these components may respond in an aberrant manner or structurally fail, resulting in unique pathological sequelae. This so-called "pathological mechanosensation" represents a spectrum of cellular responses, which vary depending on the overall biomechanical parameters of the injury and may be compounded by repetitive injuries. Such aberrant physical responses and/or damage to cells along with the resulting secondary injury cascades can ultimately lead to long-term cellular dysfunction and degeneration, often resulting in persistent deficits. Indeed, pathological mechanosensation not only directly initiates secondary injury cascades, but this post-physical damage environment provides the context in which these cascades unfold. Collectively, these points underscore the need to use experimental models that accurately replicate the biomechanics of TBI in humans. Understanding cellular responses in context with injury biomechanics may uncover therapeutic targets addressing various facets of trauma-specific sequelae.
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Affiliation(s)
- Carolyn E Keating
- Department of Neurosurgery, Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Neurotrauma, Neurodegeneration, and Restoration, Corporal Michael J. Crescenz VA Medical Center, USA
| | - D Kacy Cullen
- Department of Neurosurgery, Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA; Center for Neurotrauma, Neurodegeneration, and Restoration, Corporal Michael J. Crescenz VA Medical Center, USA.
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12
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Ho WM, Görke AS, Glodny B, Oberacher H, Helbok R, Thomé C, Petr O. Time Course of Metabolomic Alterations in Cerebrospinal Fluid After Aneurysmal Subarachnoid Hemorrhage. Front Neurol 2020; 11:589. [PMID: 32655487 PMCID: PMC7324721 DOI: 10.3389/fneur.2020.00589] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 05/22/2020] [Indexed: 11/13/2022] Open
Abstract
Object: The aim of this study was to investigate metabolite levels in cerebrospinal fluid (CSF) in their time-dependent course after aneurysmal subarachnoid hemorrhage (aSAH) comparing them to patients harboring unruptured intracranial aneurysms. Methods: Eighty CSF samples of 16 patients were analyzed. The study population included patients undergoing endovascular/microsurgical treatment of ruptured intracranial aneurysms (n = 8), which were assessed for 9 days after aSAH. Control samples were collected from the basal cisterns in elective aneurysm surgery (n = 8). The CSF samples were consecutively collected with extraventricular drain (EVD) placement/intraoperatively, 6 h later, and daily thereafter (day 1-9). The endogenous metabolites were analyzed with a targeted quantitative and quality controlled metabolomics approach using the AbsoluteIDQ®p180Kit. Differences inbetween timepoints and compared to the control group were evaluated. Results: Numerous alterations of amino acid (AA) levels were detected within the first hours after bleeding. The highest mean concentrations occurred 1 week after aSAH. AA levels were continuously increasing over time starting 6 h after aSAH. Taurine concentration was highest briefly after aSAH starting to decrease already after 6 h (vs. day 1-9, p = 0.02). The levels of sphingomyelins/ phosphatidylcholines/ lysophosphatidylcholines/mono-unsaturated fatty acid chain were highly elevated on day 0 (compared to other timepoints or controls, p < 0.01) and decreased over the next several days to concentrations comparable to the control group. Carnitine concentrations were decreased after SAH (vs. day 7, p < 0.01), while they recovered within the next day. The Fischer ratio of branched-chain AA to aromatic AA was lowest immediately after SAH and increased in 7 days (p < 0.001). Conclusion: AA levels in CSF increased overtime and often differ from patients without SAH. There was a peak concentration of structural AA within the first 6 h after aneurysm treatment. Time-dependent alterations of CSF metabolites and compounds may elucidate pathophysiological processes after aSAH, providing potential predictors assessed non-invasively by routine lab testing.
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Affiliation(s)
- Wing Mann Ho
- Department of Neurosurgery, Medical University Innsbruck, Innsbruck, Austria
| | - Alice S Görke
- Department of Neurosurgery, Medical University Innsbruck, Innsbruck, Austria
| | - Bernhard Glodny
- Department of Radiology, Medical University Innsbruck, Innsbruck, Austria
| | - Herbert Oberacher
- Department of Forensic Medicine, Medical University Innsbruck, Innsbruck, Austria
| | - Raimund Helbok
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
| | - Claudius Thomé
- Department of Neurosurgery, Medical University Innsbruck, Innsbruck, Austria
| | - Ondra Petr
- Department of Neurosurgery, Medical University Innsbruck, Innsbruck, Austria
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13
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Huguenard CJC, Cseresznye A, Evans JE, Oberlin S, Langlois H, Ferguson S, Darcey T, Nkiliza A, Dretsch M, Mullan M, Crawford F, Abdullah L. Plasma Lipidomic Analyses in Cohorts With mTBI and/or PTSD Reveal Lipids Differentially Associated With Diagnosis and APOE ε4 Carrier Status. Front Physiol 2020; 11:12. [PMID: 32082186 PMCID: PMC7005602 DOI: 10.3389/fphys.2020.00012] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 01/13/2020] [Indexed: 01/05/2023] Open
Abstract
The differential diagnosis between mild Traumatic Brain Injury (mTBI) sequelae and Post-Traumatic Stress Disorder (PTSD) is challenging due to their symptomatic overlap and co-morbidity. As such, there is a need to develop biomarkers which can help with differential diagnosis of these two conditions. Studies from our group and others suggest that blood and brain lipids are chronically altered in both mTBI and PTSD. Therefore, examining blood lipids presents a minimally invasive and cost-effective approach to identify promising biomarkers of these conditions. Using liquid chromatography-mass spectrometry (LC-MS) we examined hundreds of lipid species in the blood of healthy active duty soldiers (n = 52) and soldiers with mTBI (n = 21), PTSD (n = 34) as well as co-morbid mTBI and PTSD (n = 13) to test whether lipid levels were differentially altered with each. We also examined if the apolipoprotein E (APOE) ε4 allele can affect the association between diagnosis and peripheral lipid levels in this cohort. We show that several lipid classes are altered with diagnosis and that there is an interaction between diagnosis and the ε4 carrier status on these lipids. Indeed, total lipid levels as well as both the degree of unsaturation and chain lengths are differentially altered with diagnosis and ε4 status, specifically long chain unsaturated triglycerides (TG) and both saturated and mono-unsaturated diglycerides (DG). Additionally, an examination of lipid species reveals distinct profiles in each diagnostic group stratified by ε4 status, mainly in TG, saturated DG species and polyunsaturated phosphatidylserines. In summary, we show that peripheral lipids are promising biomarker candidates to assist with the differential diagnosis of mTBI and PTSD. Further, ε4 carrier status alone and in interaction with diagnosis has a strong influence on peripheral lipid levels. Therefore, examining ε4 status along with peripheral lipid levels could help with differential diagnosis of mTBI and PTSD.
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Affiliation(s)
- Claire J C Huguenard
- The Roskamp Institute, Sarasota, FL, United States.,School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Adam Cseresznye
- The Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - James E Evans
- The Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Sarah Oberlin
- The Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Heather Langlois
- The Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Scott Ferguson
- The Roskamp Institute, Sarasota, FL, United States.,School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Teresa Darcey
- The Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Aurore Nkiliza
- The Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Michael Dretsch
- US Army Medical Research Directorate-West, Walter Reed Army Institute of Research, Joint Base Lewis-McChord, Tacoma, WA, United States.,U.S. Army Aeromedical Research Laboratory, Fort Rucker, AL, United States
| | - Michael Mullan
- The Roskamp Institute, Sarasota, FL, United States.,School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Fiona Crawford
- The Roskamp Institute, Sarasota, FL, United States.,School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom.,James A. Haley Veterans' Hospital, Tampa, FL, United States
| | - Laila Abdullah
- The Roskamp Institute, Sarasota, FL, United States.,School of Life, Health and Chemical Sciences, The Open University, Milton Keynes, United Kingdom.,James A. Haley Veterans' Hospital, Tampa, FL, United States
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14
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Schober ME, Requena DF, Maschek JA, Cox J, Parra L, Lolofie A. Effects of controlled cortical impact and docosahexaenoic acid on rat pup fatty acid profiles. Behav Brain Res 2020; 378:112295. [PMID: 31618622 PMCID: PMC6897326 DOI: 10.1016/j.bbr.2019.112295] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/23/2019] [Accepted: 10/08/2019] [Indexed: 12/15/2022]
Abstract
Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children, particularly in those under four years old. During this period, rapid brain growth demands higher Docosahexaenoic Acid (DHA) intake. DHA is an essential fatty acid and brain cell component derived almost entirely from the diet. DHA improved neurologic outcomes and decreased inflammation after controlled cortical impact (CCI) in 17-day old (P17) rats, our established model of pediatric TBI. In adult rodents, TBI decreases brain DHA. We hypothesized that CCI would decrease rat brain DHA at post injury day (PID) 60, blunted by 0.1% DHA diet. We quantitated fatty acids using Gas Chromatography-Mass Spectrometry. We provided 0.1% DHA before CCI to ensure high DHA in dam milk. We compared brain DHA in rats after 60 days of regular (REG) or DHA diet to SHAM pups on REG diet. Brain DHA decreased in REGCCI, not in DHACCI, relative to SHAMREG. In a subsequent experiment, we gave rat pups DHA or vehicle intraperitoneally after CCI followed by DHA or REG diet for 60 days. REG increased brain Docosapentaenoic Acid (n-6 DPA, a brain DHA deficiency marker) relative to SHAMDHA and DHACCI pups (p < 0.001, diet effect). DHA diet nearly doubled DHA and decreased n-6 DPA in blood but did not increase brain DHA content (p < 0.0001, diet effect). We concluded that CCI or craniotomy alone induces a mild DHA deficit as shown by increased brain DPA.
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Affiliation(s)
- Michelle E Schober
- Department of Pediatrics, Division of Critical Care, Salt Lake City, UT, 84132, United States.
| | - Daniela F Requena
- Department of Pediatrics, Division of Critical Care, Salt Lake City, UT, 84132, United States.
| | - J Alan Maschek
- Metabolomics, Mass Spectrometry and Proteomics Core of the University of Utah, Salt Lake City, UT, 84132, United States.
| | - James Cox
- Department of Biochemistry, Salt Lake City, UT, 84132, United States; Diabetes and Metabolism Research Center, Salt Lake City, UT, 84132, United States; Metabolomics, Mass Spectrometry and Proteomics Core of the University of Utah, Salt Lake City, UT, 84132, United States.
| | - Leonardo Parra
- Department of Biology, Howard Hughes Medical Institute, Salt Lake City, UT, 84132, United States.
| | - Alyssa Lolofie
- Department of Pediatrics, Division of Critical Care, Salt Lake City, UT, 84132, United States.
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15
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Bodnar CN, Roberts KN, Higgins EK, Bachstetter AD. A Systematic Review of Closed Head Injury Models of Mild Traumatic Brain Injury in Mice and Rats. J Neurotrauma 2019; 36:1683-1706. [PMID: 30661454 PMCID: PMC6555186 DOI: 10.1089/neu.2018.6127] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Mild TBI (mTBI) is a significant health concern. Animal models of mTBI are essential for understanding mechanisms, and pathological outcomes, as well as to test therapeutic interventions. A variety of closed head models of mTBI that incorporate different aspects (i.e., biomechanics) of the mTBI have been reported. The aim of the current review was to compile a comprehensive list of the closed head mTBI rodent models, along with the common data elements, and outcomes, with the goal to summarize the current state of the field. Publications were identified from a search of PubMed and Web of Science and screened for eligibility following PRISMA guidelines. Articles were included that were closed head injuries in which the authors classified the injury as mild in rats or mice. Injury model and animal-specific common data elements, as well as behavioral and histological outcomes, were collected and compiled from a total of 402 articles. Our results outline the wide variety of methods used to model mTBI. We also discovered that female rodents and both young and aged animals are under-represented in experimental mTBI studies. Our findings will aid in providing context comparing the injury models and provide a starting point for the selection of the most appropriate model of mTBI to address a specific hypothesis. We believe this review will be a useful starting place for determining what has been done and what knowledge is missing in the field to reduce the burden of mTBI.
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Affiliation(s)
- Colleen N. Bodnar
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
| | - Kelly N. Roberts
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
| | - Emma K. Higgins
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
| | - Adam D. Bachstetter
- Department of Neuroscience, University of Kentucky, Lexington, Kentucky
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky
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16
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Anthonymuthu TS, Kenny EM, Hier ZE, Clark RSB, Kochanek PM, Kagan VE, Bayır H. Detection of brain specific cardiolipins in plasma after experimental pediatric head injury. Exp Neurol 2019; 316:63-73. [PMID: 30981805 DOI: 10.1016/j.expneurol.2019.04.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/14/2019] [Accepted: 04/10/2019] [Indexed: 12/20/2022]
Abstract
Cardiolipin (CL) is a mitochondria-specific phospholipid that is central to maintenance and regulation of mitochondrial bioenergetic and metabolic functions. CL molecular species display great tissue variation with brain exhibiting a distinct, highly diverse CL population. We recently showed that the appearance of unique brain-type CLs in plasma could serve as a brain-specific marker of mitochondrial/tissue injury in patients after cardiac arrest. Mitochondrial dysfunction has been increasingly implicated as a critical mechanism underlying the pathogenesis of traumatic brain injury (TBI). Therefore, we hypothesized that unique, brain-specific CL species from the injured brain are released to the peripheral circulation after TBI. To test this hypothesis, we performed a high-resolution mass spectrometry based phospholipidomics analysis of post-natal day (PND)17 rat brain and plasma after controlled cortical impact. We found a time-dependent increase in plasma CLs after TBI including the aforementioned brain-specific CL species early after injury, whereas CLs were significantly decreased in the injured brain. Compositional and quantitative correlational analysis suggested a possible release of CL into the systemic circulation following TBI. The identification of brain-type CLs in systemic circulation may indicate underlying mitochondrial dysfunction/loss after TBI. They may have potential as pharmacodynamics response biomarkers for targeted therapies.
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Affiliation(s)
- Tamil S Anthonymuthu
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Elizabeth M Kenny
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Zachary E Hier
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Robert S B Clark
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA
| | - Patrick M Kochanek
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA
| | - Valerian E Kagan
- Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA; Laboratory of Navigational Redox Lipidomics, IM Sechenov Moscow Medical State University, Russia
| | - Hülya Bayır
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA; Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
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17
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Ojo JO, Algamal M, Leary P, Abdullah L, Mouzon B, Evans JE, Mullan M, Crawford F. Converging and Differential Brain Phospholipid Dysregulation in the Pathogenesis of Repetitive Mild Traumatic Brain Injury and Alzheimer's Disease. Front Neurosci 2019; 13:103. [PMID: 30837829 PMCID: PMC6390207 DOI: 10.3389/fnins.2019.00103] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 01/29/2019] [Indexed: 12/14/2022] Open
Abstract
Repetitive mild traumatic brain injury (rmTBI) is a major epigenetic risk factor for Alzheimer’s disease (AD). The precise nature of how rmTBI leads to or precipitates AD pathology is currently unknown. Numerous neurological conditions have shown an important role for dysfunctional phospholipid metabolism as a driving factor for the pathogenesis of neurodegenerative diseases. However, the precise role in rmTBI and AD remains elusive. We hypothesized that a detailed phospholipid characterization would reveal profiles of response to injury in TBI that overlap with age-dependent changes in AD and thus provide insights into the TBI-AD relationship. We employed a lipidomic approach examining brain phospholipid profiles from mouse models of rmTBI and AD. Cortex and hippocampal tissue were collected at 24 h, 3, 6, 9, and 12 months post-rmTBI, and at ages representing ‘pre’, ‘peri’ and ‘post’ onset of amyloid pathology (i.e., 3, 9, 15 months-old). Total levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), LysoPE, and phosphatidylinositol (PI), including their monounsaturated, polyunsaturated and saturated fatty acid (FA) containing species were significantly increased at acute and/or chronic time points post-injury in both brain regions. However, levels of most phospholipid species in PS1/APP mice were nominal in the hippocampus, while in the cortex, levels were significantly decreased at ages post-onset of amyloid pathology. Sphingomyelin and LysoPC levels showed coincidental trends in our rmTBI and AD models within the hippocampus, an increase at acute and/or chronic time points examined. The ratio of arachidonic acid (omega-6 FA) to docosahexaenoic acid (omega-3 FA)-containing PE species was increased at early time points in the hippocampus of injured versus sham mice, and in PS1/APP mice there was a coincidental increase compared to wild type littermates at all time points. This study demonstrates some overlapping and diverse phospholipid profiles in rmTBI and AD models. Future studies are required to corroborate our findings in human post-mortem tissue. Investigation of secondary mechanisms triggered by aberrant downstream alterations in bioactive metabolites of these phospholipids, and their modulation at the appropriate time-windows of opportunity could help facilitate development of novel therapeutic strategies to ameliorate the neurodegenerative consequences of rmTBI or the potential triggering of AD pathogenesis by rmTBI.
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Affiliation(s)
- Joseph O Ojo
- Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States.,The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - Moustafa Algamal
- Roskamp Institute, Sarasota, FL, United States.,The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - Paige Leary
- Roskamp Institute, Sarasota, FL, United States
| | - Laila Abdullah
- Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States.,The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - Benoit Mouzon
- Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States.,The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | | | - Michael Mullan
- Roskamp Institute, Sarasota, FL, United States.,The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - Fiona Crawford
- Roskamp Institute, Sarasota, FL, United States.,James A. Haley Veterans' Hospital, Tampa, FL, United States.,The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
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18
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Ojo JO, Algamal M, Leary P, Abdullah L, Mouzon B, Evans JE, Mullan M, Crawford F. Disruption in Brain Phospholipid Content in a Humanized Tau Transgenic Model Following Repetitive Mild Traumatic Brain Injury. Front Neurosci 2018; 12:893. [PMID: 30564087 PMCID: PMC6288299 DOI: 10.3389/fnins.2018.00893] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 11/15/2018] [Indexed: 12/14/2022] Open
Abstract
Repetitive mild traumatic brain injury (mTBI) is a risk factor for the development of neurodegenerative diseases such as chronic traumatic encephalopathy typified by immunoreactive tau aggregates in the depths of the sulci. However, the underlying neurobiological mechanisms involved have not been largely explored. Phospholipids are important molecules which form membrane lipid bilayers; they are ubiquitous to every cell in the brain, and carry out a host of different functions. Imbalance in phospholipid metabolism, signaling and transport has been documented in some neurological conditions. However, not much is currently known about their roles in repetitive mTBI and how this may confer risk for the development of age-related neurodegenerative diseases. To address this question, we designed a longitudinal study (24 h, 3, 6, 9, and 12 months post-injury) to comprehensively investigate mTBI dependent brain phospholipid profiles compared to sham counterparts. We use our established mouse model of repetitive mTBI that has been extensively characterized up to 1-year post-injury in humanized tau (hTau) mice, which expresses all six human tau isoforms, on a null murine background. Our data indicates a significant increase in sphingomyelin, phosphatidylethanolamine (PE), phosphatidylcholine (PC), and derivative lysoPE and lysoPC at acute and/or sub-acute time points post-injury within the cortex and hippocampus. There was also a parallel increase at early time points in monounsaturated, polyunsaturated and saturated fatty acids. Omega-6 (arachidonic acid) to omega-3 (docosahexaenoic acid) fatty acid ratio for PE and PC species was increased also at 24 h and 3 months post-injury in both hippocampus and cortex. The long-term consequences of these early changes in phospholipids on neuronal and non-neuronal cell function is unclear, and warrants further study. Understanding phospholipid metabolism, signaling and transport following TBI could be valuable; they may offer novel targets for therapeutic intervention not only in TBI but other neurodegenerative diseases.
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Affiliation(s)
- Joseph O. Ojo
- Experimental Neuropathology and Omics Laboratory, Roskamp Institute, Sarasota, FL, United States
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - Moustafa Algamal
- Experimental Neuropathology and Omics Laboratory, Roskamp Institute, Sarasota, FL, United States
- The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - Paige Leary
- Experimental Neuropathology and Omics Laboratory, Roskamp Institute, Sarasota, FL, United States
| | - Laila Abdullah
- Experimental Neuropathology and Omics Laboratory, Roskamp Institute, Sarasota, FL, United States
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - Benoit Mouzon
- Experimental Neuropathology and Omics Laboratory, Roskamp Institute, Sarasota, FL, United States
- The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - James E. Evans
- Experimental Neuropathology and Omics Laboratory, Roskamp Institute, Sarasota, FL, United States
| | - Michael Mullan
- Experimental Neuropathology and Omics Laboratory, Roskamp Institute, Sarasota, FL, United States
- The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
| | - Fiona Crawford
- Experimental Neuropathology and Omics Laboratory, Roskamp Institute, Sarasota, FL, United States
- James A. Haley Veterans’ Hospital, Tampa, FL, United States
- The School of Life, Health and Chemical Sciences, Open University, Milton Keynes, United Kingdom
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19
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Chitturi J, Li Y, Santhakumar V, Kannurpatti SS. Early behavioral and metabolomic change after mild to moderate traumatic brain injury in the developing brain. Neurochem Int 2018; 120:75-86. [PMID: 30098378 DOI: 10.1016/j.neuint.2018.08.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 07/31/2018] [Accepted: 08/06/2018] [Indexed: 01/30/2023]
Abstract
Pathophysiology of developmental traumatic brain injury (TBI) is unique due to intrinsic differences in the developing brain. Energy metabolic studies of the brain during early development (P13 to P30) have indicated acute oxidative energy metabolic decreases below 24 h after TBI, which generally recovered by 48 h. However, marked neurodegeneration and altered neural functional connectivity have been observed at later stages into adolescence. As secondary neurodegeneration is most prominent during the first week after TBI in the rat model, we hypothesized that the subacute TBI-metabolome may contain predictive markers of neurodegeneration. Sham and TBI metabolomes were examined at 72 h after a mild to moderate intensity TBI in male Sprague-Dawley rats aged P31. Sensorimotor behavior was assessed at 24, 48 and 72 h after injury, followed by 72-hour postmortem brain removal for metabolomics using Liquid Chromatography/Mass Spectrometry (LC-MS) measurement. Broad TBI-induced metabolomic shifts occurred with relatively higher intensity in the injury-lateralized (ipsilateral) hemisphere. Intensity of metabolomic perturbation correlated with the extent of sensorimotor behavioral deficit. N-acetyl-aspartate (NAA) levels at 72 h after TBI, predicted the extent of neurodegeneration assessed histochemically 7-days post TBI. Results from the multivariate untargeted approach clearly distinguished metabolomic shifts induced by TBI. Several pathways including amino acid, fatty acid and energy metabolism continued to be affected at 72 h after TBI, whose collective effects may determine the overall pathological response after TBI in early development including neurodegeneration.
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Affiliation(s)
- Jyothsna Chitturi
- Department of Radiology, Rutgers New Jersey Medical School, Administrative Complex Building 5 (ADMC5), 30 Bergen Street Room 575, Newark, NJ, 07101, USA.
| | - Ying Li
- Department of Pharmacology, Physiology & Neuroscience, Rutgers New Jersey Medical School, MSB-H-512, 185 S. Orange Ave, Newark, NJ, 07103, USA.
| | - Vijayalakshmi Santhakumar
- Department of Pharmacology, Physiology & Neuroscience, Rutgers New Jersey Medical School, MSB-H-512, 185 S. Orange Ave, Newark, NJ, 07103, USA; Molecular, Cell and Systems Biology, University of California Riverside, Spieth 1308, 3401 Watkins Drive, Riverside, CA, 92521, USA.
| | - Sridhar S Kannurpatti
- Department of Radiology, Rutgers New Jersey Medical School, Administrative Complex Building 5 (ADMC5), 30 Bergen Street Room 575, Newark, NJ, 07101, USA.
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20
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Thau-Zuchman O, Gomes RN, Dyall SC, Davies M, Priestley JV, Groenendijk M, De Wilde MC, Tremoleda JL, Michael-Titus AT. Brain Phospholipid Precursors Administered Post-Injury Reduce Tissue Damage and Improve Neurological Outcome in Experimental Traumatic Brain Injury. J Neurotrauma 2018; 36:25-42. [PMID: 29768974 PMCID: PMC6306688 DOI: 10.1089/neu.2017.5579] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Traumatic brain injury (TBI) leads to cellular loss, destabilization of membranes, disruption of synapses and altered brain connectivity, and increased risk of neurodegenerative disease. A significant and long-lasting decrease in phospholipids (PLs), essential membrane constituents, has recently been reported in plasma and brain tissue, in human and experimental TBI. We hypothesized that supporting PL synthesis post-injury could improve outcome post-TBI. We tested this hypothesis using a multi-nutrient combination designed to support the biosynthesis of PLs and available for clinical use. The multi-nutrient, Fortasyn® Connect (FC), contains polyunsaturated omega-3 fatty acids, choline, uridine, vitamins, cofactors required for PL biosynthesis, and has been shown to have significant beneficial effects in early Alzheimer's disease. Male C57BL/6 mice received a controlled cortical impact injury and then were fed a control diet or a diet enriched with FC for 70 days. FC led to a significantly improved sensorimotor outcome and cognition, reduced lesion size and oligodendrocyte loss, and it restored myelin. It reversed the loss of the synaptic protein synaptophysin and decreased levels of the axon growth inhibitor, Nogo-A, thus creating a permissive environment. It decreased microglia activation and the rise in ß-amyloid precursor protein and restored the depressed neurogenesis. The effects of this medical multi-nutrient suggest that support of PL biosynthesis post-TBI, a new treatment paradigm, has significant therapeutic potential in this neurological condition for which there is no satisfactory treatment. The multi-nutrient tested has been used in dementia patients and is safe and well tolerated, which would enable rapid clinical exploration in TBI.
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Affiliation(s)
- Orli Thau-Zuchman
- 1 Centre for Neuroscience and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Rita N Gomes
- 1 Centre for Neuroscience and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Simon C Dyall
- 3 Bournemouth University, Royal London House, Bournemouth, United Kingdom
| | - Meirion Davies
- 1 Centre for Neuroscience and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - John V Priestley
- 1 Centre for Neuroscience and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Martine Groenendijk
- 2 Nutricia Research-Nutricia Advanced Medical Nutrition, Utrecht, The Netherlands
| | - Martijn C De Wilde
- 2 Nutricia Research-Nutricia Advanced Medical Nutrition, Utrecht, The Netherlands
| | - Jordi L Tremoleda
- 1 Centre for Neuroscience and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Adina T Michael-Titus
- 1 Centre for Neuroscience and Trauma, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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21
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Jayaraman SP, Anand RJ, DeAntonio JH, Mangino M, Aboutanos MB, Kasirajan V, Ivatury RR, Valadka AB, Glushakova O, Hayes RL, Bachmann LM, Brophy GM, Contaifer D, Warncke UO, Brophy DF, Wijesinghe DS. Metabolomics and Precision Medicine in Trauma: The State of the Field. Shock 2018; 50:5-13. [PMID: 29280924 PMCID: PMC5995639 DOI: 10.1097/shk.0000000000001093] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Trauma is a major problem in the United States. Mortality from trauma is the number one cause of death under the age of 45 in the United States and is the third leading cause of death for all age groups. There are approximately 200,000 deaths per year due to trauma in the United States at a cost of over $671 billion in combined healthcare costs and lost productivity. Unsurprisingly, trauma accounts for approximately 30% of all life-years lost in the United States. Due to immense development of trauma systems, a large majority of trauma patients survive the injury, but then go on to die from complications arising from the injury. These complications are marked by early and significant metabolic changes accompanied by inflammatory responses that lead to progressive organ failure and, ultimately, death. Early resuscitative and surgical interventions followed by close monitoring to identify and rescue treatment failures are key to successful outcomes. Currently, the adequacy of resuscitation is measured using vital signs, noninvasive methods such as bedside echocardiography or stroke volume variation, and other laboratory endpoints of resuscitation, such as lactate and base deficit. However, these methods may be too crude to understand cellular and subcellular changes that may be occurring in trauma patients. Better diagnostic and therapeutic markers are needed to assess the adequacy of interventions and monitor responses at a cellular and subcellular level and inform clinical decision-making before complications are clinically apparent. The developing field of metabolomics holds great promise in the identification and application of biochemical markers toward the clinical decision-making process.
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Affiliation(s)
- Sudha P Jayaraman
- Department of Surgery, Division of Acute Care Surgical Services, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Rahul J Anand
- Department of Surgery, Division of Acute Care Surgical Services, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Jonathan H DeAntonio
- Department of Surgery, Division of Acute Care Surgical Services, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Martin Mangino
- Department of Surgery, Division of Acute Care Surgical Services, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Michel B Aboutanos
- Department of Surgery, Division of Acute Care Surgical Services, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Vigneshwar Kasirajan
- Department of Surgery, Division of Cardiothoracic Surgery, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Rao R Ivatury
- Department of Surgery, Division of Acute Care Surgical Services, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Alex B Valadka
- Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Olena Glushakova
- Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Ronald L Hayes
- Department of Neurosurgery, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
- Center of Innovative Research, Banyan Biomarkers, Inc., Alachua, Florida
| | - Lorin M Bachmann
- Department of Pathology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Gretchen M Brophy
- Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia
| | - Daniel Contaifer
- Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia
| | - Urszula O Warncke
- Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia
| | - Donald F Brophy
- Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia
| | - Dayanjan S Wijesinghe
- Department of Surgery, Division of Acute Care Surgical Services, School of Medicine, Virginia Commonwealth University, Richmond, Virginia
- Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia
- da Vinci Center, Virginia Commonwealth University, Richmond, Virginia
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22
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Moyron RB, Wall NR. Differential protein expression in exosomal samples taken from trauma patients. Proteomics Clin Appl 2018; 11. [PMID: 28734082 DOI: 10.1002/prca.201700095] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Revised: 06/18/2017] [Accepted: 07/14/2017] [Indexed: 11/08/2022]
Affiliation(s)
- Ron B Moyron
- Center for Health Disparities Research and Molecular Medicine, Loma Linda University, Loma Linda, CA, USA.,Department of Basic Sciences, Division of Biochemistry, Loma Linda University, Loma Linda, CA, USA
| | - Nathan R Wall
- Center for Health Disparities Research and Molecular Medicine, Loma Linda University, Loma Linda, CA, USA.,Department of Basic Sciences, Division of Biochemistry, Loma Linda University, Loma Linda, CA, USA
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23
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Ercole A, Magnoni S, Vegliante G, Pastorelli R, Surmacki J, Bohndiek SE, Zanier ER. Current and Emerging Technologies for Probing Molecular Signatures of Traumatic Brain Injury. Front Neurol 2017; 8:450. [PMID: 28912750 PMCID: PMC5582086 DOI: 10.3389/fneur.2017.00450] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 08/14/2017] [Indexed: 01/10/2023] Open
Abstract
Traumatic brain injury (TBI) is understood as an interplay between the initial injury, subsequent secondary injuries, and a complex host response all of which are highly heterogeneous. An understanding of the underlying biology suggests a number of windows where mechanistically inspired interventions could be targeted. Unfortunately, biologically plausible therapies have to-date failed to translate into clinical practice. While a number of stereotypical pathways are now understood to be involved, current clinical characterization is too crude for it to be possible to characterize the biological phenotype in a truly mechanistically meaningful way. In this review, we examine current and emerging technologies for fuller biochemical characterization by the simultaneous measurement of multiple, diverse biomarkers. We describe how clinically available techniques such as cerebral microdialysis can be leveraged to give mechanistic insights into TBI pathobiology and how multiplex proteomic and metabolomic techniques can give a more complete description of the underlying biology. We also describe spatially resolved label-free multiplex techniques capable of probing structural differences in chemical signatures. Finally, we touch on the bioinformatics challenges that result from the acquisition of such large amounts of chemical data in the search for a more mechanistically complete description of the TBI phenotype.
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Affiliation(s)
- Ari Ercole
- Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Sandra Magnoni
- Department of Anesthesiology and Intensive Care, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Gloria Vegliante
- Laboratory of Acute Brain Injury and Therapeutic Strategies, Department of Neuroscience, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Roberta Pastorelli
- Unit of Gene and Protein Biomarkers, Laboratory of Mass Spectrometry, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Jakub Surmacki
- Department of Physics, University of Cambridge, Cambridge, United Kingdom
| | - Sarah Elizabeth Bohndiek
- Department of Physics, University of Cambridge, Cambridge, United Kingdom
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
| | - Elisa R. Zanier
- Laboratory of Acute Brain Injury and Therapeutic Strategies, Department of Neuroscience, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
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24
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Posti JP, Dickens AM, Orešič M, Hyötyläinen T, Tenovuo O. Metabolomics Profiling As a Diagnostic Tool in Severe Traumatic Brain Injury. Front Neurol 2017; 8:398. [PMID: 28868043 PMCID: PMC5563327 DOI: 10.3389/fneur.2017.00398] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 07/25/2017] [Indexed: 12/16/2022] Open
Abstract
Traumatic brain injury (TBI) is a complex disease with a multifaceted pathophysiology. Impairment of energy metabolism is a key component of secondary insults. This phenomenon is a consequence of multiple potential mechanisms including diffusion hypoxia, mitochondrial failure, and increased energy needs due to systemic trauma responses, seizures, or spreading depolarization. The degree of disturbance in brain metabolism is affected by treatment interventions and reflected in clinical patient outcome. Hence, monitoring of these secondary events in peripheral blood will provide a window into the pathophysiological course of severe TBI. New methods for assessing perturbation of brain metabolism are needed in order to monitor on-going pathophysiological processes and thus facilitate targeted interventions and predict outcome. Circulating metabolites in peripheral blood may serve as sensitive markers of pathological processes in TBI. The levels of these small molecules in blood are less dependent on the integrity of the blood–brain barrier as compared to protein biomarkers. We have recently characterized a specific metabolic profile in serum that is associated with both initial severity and patient outcome of TBI. We found that two medium-chain fatty acids, octanoic and decanoic acids, as well as several sugar derivatives are significantly associated with the severity of TBI. The top ranking peripheral blood metabolites were also highly correlated with their levels in cerebral microdialyzates. Based on the metabolite profile upon admission, we have been able to develop a model that accurately predicts patient outcome. Moreover, metabolomics profiling improved the performance of the well-established clinical prognostication model. In this review, we discuss metabolomics profiling in patients with severe TBI. We present arguments in support of the need for further development and validation of circulating biomarkers of cerebral metabolism and for their use in assessing patients with severe TBI.
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Affiliation(s)
- Jussi P Posti
- Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland.,Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland.,Department of Neurology, University of Turku, Turku, Finland
| | - Alex M Dickens
- Turku Centre for Biotechnology, University of Turku, Turku, Finland
| | - Matej Orešič
- Turku Centre for Biotechnology, University of Turku, Turku, Finland
| | | | - Olli Tenovuo
- Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland.,Department of Neurology, University of Turku, Turku, Finland
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25
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Monitoring changes of docosahexaenoic acid-containing lipids during the recovery process of traumatic brain injury in rat using mass spectrometry imaging. Sci Rep 2017; 7:5054. [PMID: 28698592 PMCID: PMC5506011 DOI: 10.1038/s41598-017-05446-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 05/30/2017] [Indexed: 01/13/2023] Open
Abstract
Brain lipid homoeostasis is critical during recovery process after traumatic brain injury (TBI). In this study, we integrated liquid extraction and electrosonic spray ionization technology to develop an ionization device coupled with a Fourier transform ion cyclotron resonance mass spectrometer for imaging of docosahexaenoic acid (DHA)-containing lipids on rat brain tissues. The ion images of the brain tissue sections from the normal rats and the rats after TBI at acute phase (0 and 1 day) and chronic phase (3, 5, and 7 days) were obtained. The imaging results indicate that the levels of DHA and lyso-phosphatidylethanolamine (22:6) in the injury area of TBI rats increased significantly at the acute phase and subsequently decreased at the chronic phase. But the levels of DHA-containing phospholipids including phosphatidylethanolamine (PE)(P-18:0/22:6), PE(18:0/22:6), and phosphatidylserine (18:0/22:6) decreased at the acute phase and gradually increased at the chronic phase in the injury area accompanied by the morphogenesis and wound healing. These findings indicate that the DHA may participate in the recovery process of brain injury. This is the first report to in situ detect the changes in the levels of DHA and DHA-containing lipids in the TBI model.
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26
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Phospholipid profiling of plasma from GW veterans and rodent models to identify potential biomarkers of Gulf War Illness. PLoS One 2017; 12:e0176634. [PMID: 28453542 PMCID: PMC5409146 DOI: 10.1371/journal.pone.0176634] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 04/13/2017] [Indexed: 12/20/2022] Open
Abstract
Gulf War Illness (GWI), which affects at least one fourth of the 700,000 veterans deployed to the Gulf War (GW), is characterized by persistent and heterogeneous symptoms, including pain, fatigue and cognitive problems. As a consequence, this illness remains difficult to diagnose. Rodent models have been shown to exhibit different symptomatic features of GWI following exposure to particular GW agents (e.g. pyridostigmine bromide, permethrin and DEET) and/or stress. Preclinical analyses have shown the activation of microglia and astroglia as a pathological hallmark in these mouse and rat models. Although much has been learned in recent years from these different rodent models and independent clinical studies, characterization studies to identify overlapping features of GWI in animals and humans have been missing. Thus, we aimed to identify biomarkers that co-occur in the plasma of rodent models of GWI and human GWI patients. We observed increases of multiple phospholipid (PL) species across all studied cohorts. Furthermore, these data suggested dysfunction within ether and docosahexaenoic acid and arachidonic acid containing PL species in relation to GWI. As these PL species play a role in inflammatory processes, these findings suggest a possible role for inflammatory imbalance in GWI. Overall, we show that the peripheral lipid disturbances are present both in human GWI patients and in the preclinical rodent models of GWI, highlighting the importance of lipidomics as a potential platform for further biomarker discovery and supporting the value of GW agent exposed models of GWI.
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