Skip to main content
Top
Published in: Alzheimer's Research & Therapy 1/2015

Open Access 01-12-2015 | Research

Changes in the neurochemistry of athletes with repetitive brain trauma: preliminary results using localized correlated spectroscopy

Authors: Alexander P Lin, Saadallah Ramadan, Robert A Stern, Hayden C Box, Christopher J Nowinski, Brian D Ross, Carolyn E Mountford

Published in: Alzheimer's Research & Therapy | Issue 1/2015

Login to get access

Abstract

Introduction

The goal was to identify which neurochemicals differ in professional athletes with repetitive brain trauma (RBT) when compared to healthy controls using a relatively new technology, in vivo Localized COrrelated SpectroscopY (L-COSY).

Methods

To achieve this, L-COSY was used to examine five former professional male athletes with 11 to 28 years of exposure to contact sports. Each athlete who had had multiple symptomatic concussions and repetitive sub concussive trauma during their career was assessed by an experienced neuropsychologist. All athletes had clinical symptoms including headaches, memory loss, confusion, impaired judgment, impulse control problems, aggression, and depression. Five healthy men, age and weight matched to the athlete cohort and with no history of brain trauma, were recruited as controls. Data were collected from the posterior cingulate gyrus using a 3 T clinical magnetic resonance scanner equipped with a 32 channel head coil.

Results

The variation of the method was calculated by repeated examination of a healthy control and phantom and found to be 10% and 5%, respectively, or less. The L-COSY measured large and statistically significant differences (P ≤0.05), between healthy controls and those athletes with RBT. Men with RBT showed higher levels of glutamine/glutamate (31%), choline (65%), fucosylated molecules (60%) and phenylalanine (46%). The results were evaluated and the sample size of five found to achieve a significance level P = 0.05 and a power of 90%. Differences in N-acetyl aspartate and myo-inositol between RBT and controls were small and were not statistically significance.

Conclusions

A study of a small cohort of professional athletes, with a history of RBT and symptoms of chronic traumatic encephalopathy when compared with healthy controls using 2D L-COSY, showed elevations in brain glutamate/glutamine and choline as recorded previously for early traumatic brain injury. For the first time increases in phenylalanine and fucose are recorded in the brains of athletes with RBT. Larger studies utilizing the L-COSY method may offer an in-life method of diagnosis and personalized approach for monitoring the acute effects of mild traumatic brain injury and the chronic effects of RBT.
Literature
1.
go back to reference Gavett BE, Cantu RC, Shenton M, Lin AP, Nowinski CJ, McKee AC, et al. Clinical appraisal of chronic traumatic encephalopathy: current perspectives and future directions. Curr Opin Neurol. 2011;24:525–31.CrossRefPubMed Gavett BE, Cantu RC, Shenton M, Lin AP, Nowinski CJ, McKee AC, et al. Clinical appraisal of chronic traumatic encephalopathy: current perspectives and future directions. Curr Opin Neurol. 2011;24:525–31.CrossRefPubMed
2.
go back to reference Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;81:1122–9.CrossRefPubMedCentralPubMed Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;81:1122–9.CrossRefPubMedCentralPubMed
3.
go back to reference McKee A, Cantu R, Nowinski C, Hedley-Whyte E, Gavett B, Budson A, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68:709–35.CrossRefPubMedCentralPubMed McKee A, Cantu R, Nowinski C, Hedley-Whyte E, Gavett B, Budson A, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68:709–35.CrossRefPubMedCentralPubMed
4.
go back to reference McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Lee HS, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2012;136:43–64.CrossRefPubMedCentralPubMed McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Lee HS, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2012;136:43–64.CrossRefPubMedCentralPubMed
5.
go back to reference Mountford CE, Stanwell P, Lin A, Ramadan S, Ross B. Neurospectroscopy: the past, present and future. Chem Rev. 2010;110:3060–86.CrossRefPubMed Mountford CE, Stanwell P, Lin A, Ramadan S, Ross B. Neurospectroscopy: the past, present and future. Chem Rev. 2010;110:3060–86.CrossRefPubMed
6.
go back to reference Jansen JF, Backes WH, Nicolay K, Kooi ME. H-1 MR spectroscopy of the brain: absolute quantification of metabolites. Radiology. 2006;240:318–32.CrossRefPubMed Jansen JF, Backes WH, Nicolay K, Kooi ME. H-1 MR spectroscopy of the brain: absolute quantification of metabolites. Radiology. 2006;240:318–32.CrossRefPubMed
7.
go back to reference Kaiser LG, Marjanska M, Matson GB, Iltis I, Bush SD, Soher BJ, et al. 1H MRS detection of glycine residue of reduced glutathione in vivo. J Magn Reson B. 2010;202:259–66.CrossRef Kaiser LG, Marjanska M, Matson GB, Iltis I, Bush SD, Soher BJ, et al. 1H MRS detection of glycine residue of reduced glutathione in vivo. J Magn Reson B. 2010;202:259–66.CrossRef
8.
go back to reference Snyder J, Wilman A. Field strength dependence of PRESS timings for simultaneous detection of glutamate and glutamine from 1.5 to 7 T. J Magn Reson B. 2010;203:66–72.CrossRef Snyder J, Wilman A. Field strength dependence of PRESS timings for simultaneous detection of glutamate and glutamine from 1.5 to 7 T. J Magn Reson B. 2010;203:66–72.CrossRef
9.
go back to reference Henry LC, Tremblay S, Boulanger Y, Ellemberg D, Lassonde M. Neurometabolic changes in the acute phase after sports concussions correlate with symptom severity. J Neurotrauma. 2010;27:65–76.CrossRefPubMed Henry LC, Tremblay S, Boulanger Y, Ellemberg D, Lassonde M. Neurometabolic changes in the acute phase after sports concussions correlate with symptom severity. J Neurotrauma. 2010;27:65–76.CrossRefPubMed
10.
go back to reference Vagnozzi R, Signoretti S, Cristofori L, Alessandrini F, Floris R, Isgrò E, et al. Assessment of metabolic brain damage and recovery following mild traumatic brain injury: a multicentre, proton magnetic resonance spectroscopic study in concussed patients. Brain. 2010;133:3232–42.CrossRefPubMed Vagnozzi R, Signoretti S, Cristofori L, Alessandrini F, Floris R, Isgrò E, et al. Assessment of metabolic brain damage and recovery following mild traumatic brain injury: a multicentre, proton magnetic resonance spectroscopic study in concussed patients. Brain. 2010;133:3232–42.CrossRefPubMed
11.
go back to reference Ramadan S, Andronesi O, Stanwell P, Lin A, Sorenson G, Mountford C. In vivo two dimensional MR spectroscopy compares the biochemistry of the human brain and glioblastoma. Radiology. 2011;259:540–9.CrossRefPubMedCentralPubMed Ramadan S, Andronesi O, Stanwell P, Lin A, Sorenson G, Mountford C. In vivo two dimensional MR spectroscopy compares the biochemistry of the human brain and glioblastoma. Radiology. 2011;259:540–9.CrossRefPubMedCentralPubMed
12.
go back to reference Thomas M, Yue K, Binesh N, Davanzo P, Kumar A, Siegel B, et al. Localized two-dimensional shift correlated MR spectroscopy of human brain. Magn Reson Med. 2001;46:58–67.CrossRefPubMed Thomas M, Yue K, Binesh N, Davanzo P, Kumar A, Siegel B, et al. Localized two-dimensional shift correlated MR spectroscopy of human brain. Magn Reson Med. 2001;46:58–67.CrossRefPubMed
13.
go back to reference Ramadan S, Mountford CE, Mulkern R. w-3 fatty acid detection by L-COSY in human bone marrow at 3T [abstract]. In: Proceedings of the International Society of Magnetic Resonance in Medicine: 2010. Stockholm, Sweden: Wiley; 2010. p. 1478. Ramadan S, Mountford CE, Mulkern R. w-3 fatty acid detection by L-COSY in human bone marrow at 3T [abstract]. In: Proceedings of the International Society of Magnetic Resonance in Medicine: 2010. Stockholm, Sweden: Wiley; 2010. p. 1478.
14.
go back to reference Velan SS, Lemieux SK, Raylman RR, Boling W, Hobbs GR, Spencer RG, et al. Detection of cerebral metabolites by single-voxel-based PRESS and COSY techniques at 3 T. J Magn Reson Imaging. 2007;26:405–9.CrossRefPubMed Velan SS, Lemieux SK, Raylman RR, Boling W, Hobbs GR, Spencer RG, et al. Detection of cerebral metabolites by single-voxel-based PRESS and COSY techniques at 3 T. J Magn Reson Imaging. 2007;26:405–9.CrossRefPubMed
15.
go back to reference Ashwal S, Holshouser BA, Shu SK, Simmons PL, Perkin RM, Tomasi LG, et al. Predictive value of proton magnetic resonance spectroscopy in pediatric closed head injury. Pediatr Neurol. 2000;23:114–25.CrossRefPubMed Ashwal S, Holshouser BA, Shu SK, Simmons PL, Perkin RM, Tomasi LG, et al. Predictive value of proton magnetic resonance spectroscopy in pediatric closed head injury. Pediatr Neurol. 2000;23:114–25.CrossRefPubMed
16.
go back to reference Ross BD, Ernst T, Kreis R, Haseler LJ, Bayer S, Danielsen E, et al. 1H MRS in acute traumatic brain injury. J Magn Reson Imaging. 1998;8:829–40.CrossRefPubMed Ross BD, Ernst T, Kreis R, Haseler LJ, Bayer S, Danielsen E, et al. 1H MRS in acute traumatic brain injury. J Magn Reson Imaging. 1998;8:829–40.CrossRefPubMed
17.
go back to reference Ogg R, Kinglsey P, Taylor J. WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy. J Magn Reson B. 1994;104:1–10.CrossRefPubMed Ogg R, Kinglsey P, Taylor J. WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy. J Magn Reson B. 1994;104:1–10.CrossRefPubMed
18.
go back to reference MATLAB and Statistics Toolbox Release 7.01.24704(R14). The MathWorks, Inc., Natick, Massachusetts, US. MATLAB and Statistics Toolbox Release 7.01.24704(R14). The MathWorks, Inc., Natick, Massachusetts, US.
19.
go back to reference Delikatny EJ, Hull WE, Mountford CE. The effect of altering time domains and window functions in two-dimensional proton COSY spectra of biological specimens. J Magn Reson. 1991;94:463–73. Delikatny EJ, Hull WE, Mountford CE. The effect of altering time domains and window functions in two-dimensional proton COSY spectra of biological specimens. J Magn Reson. 1991;94:463–73.
20.
go back to reference Govindaraju V, Young K, Maudsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 2000;13:129–53.CrossRefPubMed Govindaraju V, Young K, Maudsley AA. Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed. 2000;13:129–53.CrossRefPubMed
21.
go back to reference Lean CL, Mackinnon WB, Delikatny EJ, Whitehead RH, Mountford CE. Cell-surface fucosylation and magnetic resonance spectroscopy characterization of human malignant colorectal cells. Biochemistry. 1992;31:11095–105.CrossRefPubMed Lean CL, Mackinnon WB, Delikatny EJ, Whitehead RH, Mountford CE. Cell-surface fucosylation and magnetic resonance spectroscopy characterization of human malignant colorectal cells. Biochemistry. 1992;31:11095–105.CrossRefPubMed
23.
go back to reference Kierans AS, Kirov II, Gonen O, Haemer G, Nisenbaum E, Babb JS, et al. Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury. Neurology. 2014;82:521–8.CrossRefPubMedCentralPubMed Kierans AS, Kirov II, Gonen O, Haemer G, Nisenbaum E, Babb JS, et al. Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury. Neurology. 2014;82:521–8.CrossRefPubMedCentralPubMed
24.
go back to reference Kirov II, Tal A, Babb JS, Reaume J, Bushnik T, Ashman TA, et al. Proton MR spectroscopy correlates diffuse axonal abnormalities with post-concussive symptoms in mild traumatic brain injury. J Neurotrauma. 2013;30:1200–4.CrossRefPubMedCentralPubMed Kirov II, Tal A, Babb JS, Reaume J, Bushnik T, Ashman TA, et al. Proton MR spectroscopy correlates diffuse axonal abnormalities with post-concussive symptoms in mild traumatic brain injury. J Neurotrauma. 2013;30:1200–4.CrossRefPubMedCentralPubMed
25.
go back to reference Lean CL, Mackinnon WB, Mountford CE. Fucose in 1H COSY spectra of plasma membrane fragments shed from human malignant colorectal cells. Magn Reson Med. 1991;20:306–11.CrossRefPubMed Lean CL, Mackinnon WB, Mountford CE. Fucose in 1H COSY spectra of plasma membrane fragments shed from human malignant colorectal cells. Magn Reson Med. 1991;20:306–11.CrossRefPubMed
26.
go back to reference Murrey HE, Ficarro SB, Krishnamurthy C, Domino SE, Peters EC, Hsieh-Wilson LC. Identification of the plasticity-relevant fucose-α(1–2)-galactose proteome from the mouse olfactory bulb. Biochemistry. 2009;48:7261–70.CrossRefPubMedCentralPubMed Murrey HE, Ficarro SB, Krishnamurthy C, Domino SE, Peters EC, Hsieh-Wilson LC. Identification of the plasticity-relevant fucose-α(1–2)-galactose proteome from the mouse olfactory bulb. Biochemistry. 2009;48:7261–70.CrossRefPubMedCentralPubMed
27.
go back to reference Brooks WM, Stidley CA, Petropoulos H, Jung RE, Weers DC, Friedman SD, et al. Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J Neurotrauma. 2000;17:629–40.CrossRefPubMed Brooks WM, Stidley CA, Petropoulos H, Jung RE, Weers DC, Friedman SD, et al. Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J Neurotrauma. 2000;17:629–40.CrossRefPubMed
28.
go back to reference Shutter L, Tong KA, Holshouser BA. Proton MRS in acute traumatic brain injury: role for glutamate/glutamine and choline for outcome prediction. J Neurotrauma. 2004;21:1693–705.CrossRefPubMed Shutter L, Tong KA, Holshouser BA. Proton MRS in acute traumatic brain injury: role for glutamate/glutamine and choline for outcome prediction. J Neurotrauma. 2004;21:1693–705.CrossRefPubMed
29.
go back to reference Lin AP, Liao HJ, Merugumala SK, Prabhu SP, Meehan 3rd WP, Ross BD. Metabolic imaging of mild traumatic brain injury. Brain Imaging Behav. 2012;6:208–23.CrossRefPubMed Lin AP, Liao HJ, Merugumala SK, Prabhu SP, Meehan 3rd WP, Ross BD. Metabolic imaging of mild traumatic brain injury. Brain Imaging Behav. 2012;6:208–23.CrossRefPubMed
30.
go back to reference Chamoun R, Suki D, Gopinath SP, Goodman JC, Robertson C. Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J Neurosurg. 2010;113:564–70.CrossRefPubMedCentralPubMed Chamoun R, Suki D, Gopinath SP, Goodman JC, Robertson C. Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J Neurosurg. 2010;113:564–70.CrossRefPubMedCentralPubMed
31.
go back to reference Lee M. Neurotransmitters and microglial-mediated neuroinflammation. Curr Protein Pept Sci. 2013;14:21–32.CrossRefPubMed Lee M. Neurotransmitters and microglial-mediated neuroinflammation. Curr Protein Pept Sci. 2013;14:21–32.CrossRefPubMed
32.
go back to reference Nagarajan RS, Thames AD, Castellon SA, Hinkin CH, Thomas MA. 2D MR spectroscopy combined with prior-knowledge fitting is sensitive to HCV-associated cerebral metabolic abnormalities. Int J Hepatol. 2012;2012:179365.CrossRefPubMedCentralPubMed Nagarajan RS, Thames AD, Castellon SA, Hinkin CH, Thomas MA. 2D MR spectroscopy combined with prior-knowledge fitting is sensitive to HCV-associated cerebral metabolic abnormalities. Int J Hepatol. 2012;2012:179365.CrossRefPubMedCentralPubMed
33.
go back to reference Kumar A, Loane DJ. Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun. 2012;26:1191–201.CrossRefPubMed Kumar A, Loane DJ. Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun. 2012;26:1191–201.CrossRefPubMed
34.
go back to reference Ojo JO, Mouzon B, Greenberg MB, Bachmeier C, Mullan M, Crawford F. Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice. J Neuropathol Exp Neurol. 2013;72:137–51.CrossRefPubMed Ojo JO, Mouzon B, Greenberg MB, Bachmeier C, Mullan M, Crawford F. Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice. J Neuropathol Exp Neurol. 2013;72:137–51.CrossRefPubMed
36.
go back to reference Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, et al. Clinical presentation and ApoE genotype of neuropathologically confirmed chronic traumatic encephalopathy in athletes. Neurology. 2013;81:1122–9.CrossRefPubMedCentralPubMed Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, et al. Clinical presentation and ApoE genotype of neuropathologically confirmed chronic traumatic encephalopathy in athletes. Neurology. 2013;81:1122–9.CrossRefPubMedCentralPubMed
37.
38.
39.
go back to reference Holshouser BA, Tong KA, Ashwal S. Proton MR spectroscopic imaging depicts diffuse axonal injury in children with traumatic brain injury. AJNR Am J Neuroradiol. 2005;26:1276–85.PubMed Holshouser BA, Tong KA, Ashwal S. Proton MR spectroscopic imaging depicts diffuse axonal injury in children with traumatic brain injury. AJNR Am J Neuroradiol. 2005;26:1276–85.PubMed
40.
go back to reference De Graaf TW, der Stelt V, Anbergen MG, van Dijk W. Inflammation-induced expression of sialyl Lewis X-containing glycan structures on alpha 1-acid glycoprotein (orosomucoid) in human sera. J Experimental Med. 1993;177:657–66.CrossRef De Graaf TW, der Stelt V, Anbergen MG, van Dijk W. Inflammation-induced expression of sialyl Lewis X-containing glycan structures on alpha 1-acid glycoprotein (orosomucoid) in human sera. J Experimental Med. 1993;177:657–66.CrossRef
41.
go back to reference Smalla KH, Angenstein F, Richter K, Gundelfinger ED, Staak S. Identification of fucose-alpha[1–2]-galactose epitope-containing glycoproteins from rat hippocampus. Neuroreport. 1998;9:813–7.CrossRefPubMed Smalla KH, Angenstein F, Richter K, Gundelfinger ED, Staak S. Identification of fucose-alpha[1–2]-galactose epitope-containing glycoproteins from rat hippocampus. Neuroreport. 1998;9:813–7.CrossRefPubMed
43.
go back to reference Lowe JB. Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr Opin Cell Biol. 2003;15:531–8.CrossRefPubMed Lowe JB. Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr Opin Cell Biol. 2003;15:531–8.CrossRefPubMed
44.
go back to reference Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 2011;70:374–83.CrossRefPubMed Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 2011;70:374–83.CrossRefPubMed
45.
go back to reference Bagchi SP, Smith TM. Dopamine formation from phenylalanine: independent existence in caudate nucleus synaptosomes. J Neural Transm. 1977;41:101–7.CrossRefPubMed Bagchi SP, Smith TM. Dopamine formation from phenylalanine: independent existence in caudate nucleus synaptosomes. J Neural Transm. 1977;41:101–7.CrossRefPubMed
46.
go back to reference Sharman R, Sullivan K, Young RM, McGill J. Depressive symptoms in adolescents with early and continuously treated phenylketonuria: associations with phenylalanine and tyrosine levels. Gene. 2012;504:288–91.CrossRefPubMed Sharman R, Sullivan K, Young RM, McGill J. Depressive symptoms in adolescents with early and continuously treated phenylketonuria: associations with phenylalanine and tyrosine levels. Gene. 2012;504:288–91.CrossRefPubMed
47.
go back to reference Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, et al. Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology. 2000;55:1158–66.CrossRefPubMed Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, et al. Documented head injury in early adulthood and risk of Alzheimer’s disease and other dementias. Neurology. 2000;55:1158–66.CrossRefPubMed
48.
go back to reference Schofield PW, Tang M, Marder K, Bell K, Dooneief G, Chun M, et al. Alzheimer’s disease after remote head injury: an incidence study. J Neurol Neurosurg Psychiatry. 1997;62:119–24.CrossRefPubMedCentralPubMed Schofield PW, Tang M, Marder K, Bell K, Dooneief G, Chun M, et al. Alzheimer’s disease after remote head injury: an incidence study. J Neurol Neurosurg Psychiatry. 1997;62:119–24.CrossRefPubMedCentralPubMed
49.
go back to reference Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired national football league players. Neurology. 2012;79:1970–4.CrossRefPubMedCentralPubMed Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired national football league players. Neurology. 2012;79:1970–4.CrossRefPubMedCentralPubMed
50.
Metadata
Title
Changes in the neurochemistry of athletes with repetitive brain trauma: preliminary results using localized correlated spectroscopy
Authors
Alexander P Lin
Saadallah Ramadan
Robert A Stern
Hayden C Box
Christopher J Nowinski
Brian D Ross
Carolyn E Mountford
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2015
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-015-0094-5

Other articles of this Issue 1/2015

Alzheimer's Research & Therapy 1/2015 Go to the issue