Metabolic Brain Disease

, Volume 26, Issue 3, pp 173–184 | Cite as

Multi-dimensional MR spectroscopy: towards a better understanding of hepatic encephalopathy

  • Manoj K. Sarma
  • Amir Huda
  • Rajakumar Nagarajan
  • Charles H. Hinkin
  • Neil Wilson
  • Rakesh K. Gupta
  • Enrique Frias-Martinez
  • James Sayre
  • Barry Guze
  • Steven-Huy Han
  • M. Albert Thomas
Original Paper

Abstract

Hepatic encephalopathy (HE) is normally diagnosed by neuropsychological (NP) tests. The goals of this study were to quantify cerebral metabolites, separate glutamate (Glu) from glutamine (Gln) in patients with minimal hepatic encephalopathy (MHE) as well as healthy subjects using the prior-knowledge fitting (ProFit) algorithm on data acquired by two-dimensional (2D) localized correlated spectroscopy (L-COSY) on two different MR scanners, and to correlate the metabolite changes with neuropsychological (NP) tests. We studied 14 MHE patients and 18 healthy controls using a GE 1.5 T Signa MR scanner. Another group of 16 MHE patients and 18 healthy controls were studied using a Siemens 1.5 T Avanto MR scanner. The following parameters were used for L-COSY: TR/TE = 2 s/30 ms, 3 × 3 × 3 cm3 voxel size, 96 Δt1 increments with 8 averages per Δt1. Using the ProFit algorithm, we were able to differentiate Gln from Glu on the GE 1.5 T data in the medial frontal white/gray matter. The ratios of myo-inositol (mI), Glu, total choline, scyllo-inositol (sI), phosphoethanolamine (PE), and total N-acetyl aspartate (NAA) showed statistically significant decline in HE patients compared to healthy controls, while the ratio of Gln was significantly increased. Similar trend was seen in the ProFit quantified Siemens 1.5 T data in the frontal and occipito-parietal white/gray regions. Among the NP domain scores, motor function, cognitive speed, executive function and the global scores showed significant differences. Excellent correlations between various NP domains and metabolite ratios were also observed. ProFit based cerebral metabolite quantitation enhances the understanding and basis of the current hypothesis of MHE.

Keywords

MRS COSY Hepatic encephalopathy Glutamine Glutamate Neuropsychological tests 

References

  1. Amodio P, Del Piccolo F, Marchetti P, Angeli P, Iemmolo R, Caregaro L, Merkel C, Gerunda G, Gatta A (1999) Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology 29:1662–1667PubMedCrossRefGoogle Scholar
  2. Amodio P, Del Piccolo F, Pettenò E, Mapelli D, Angeli P, Iemmolo R, Muraca M, Musto C, Gerunda G, Rizzo C, Merkel C, Gatta A (2001) Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. J Hepatol 35:37–45PubMedCrossRefGoogle Scholar
  3. Amodio P, Montagnese S, Gatta A, Morgan MY (2004) Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 19:253–267PubMedCrossRefGoogle Scholar
  4. Amodio P, Ridola L, Schiff S, Montagnese S, Pasquale C, Nardelli S, Pentassuglio I, Trezza M, Marzano C, Flaiban C, Angeli P, Cona G, Bisiacchi P, Gatta A, Riggio O (2010) Improving detection of minimal hepatic encephalopathy using the inhibitory control task. Gastroenterology 139:510–518PubMedCrossRefGoogle Scholar
  5. Berl S, Tokagaki G, Clarke DD, Waelsch H (1962) Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver. J Biol Chem 237:2562–2569PubMedGoogle Scholar
  6. Bernthal P, Hayes A, Tarter RE, Van Thiel D, Lecky J, Hegedus A (1987) Cerebral CT scan abnormalities in cholestatic and hepatocellular disease and their relationship to neuropsychologic test performance. Hepatology 7:107–114PubMedCrossRefGoogle Scholar
  7. Bhujwalla ZM, Aboagye EO, Gillies RJ, Chacko VP, Mendola CE, Backer JM (1999) Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo and in vitro. Magn Reson Med 41:897–903PubMedCrossRefGoogle Scholar
  8. Binesh N, Huda A, Bugbee M, Gupta R, Rasgon N, Kumar A, Green M, Han S, Thomas MA (2005) Adding another spectral dimension to 1H magnetic resonance spectroscopy of hepatic encephalopathy. J Magn Reson Imaging 21:398–405PubMedCrossRefGoogle Scholar
  9. Binesh N, Huda A, Thomas MA, Wyckoff N, Bugbee M, Han S, Rasgon N, Davanzo P, Sayre J, Guze B, Martin P, Fawzy F (2006) Hepatic encephalopathy: a neurochemical, neuroanatomical, and neuropsychological study. J Appl Clin Med Phys 7:86–96PubMedCrossRefGoogle Scholar
  10. Blei AT, Cordoba J (1996) Subclinical encephalopathy. Digest Dis 14:2–11CrossRefGoogle Scholar
  11. Bosman DK, Deutz NE, De Graaf AA, vd Hulst RW, Van Eijk HM, Bovée WM, Maas MA, Jörning GG, Chamuleau RA (1990) Changes in brain metabolism during hyperammonemia and acute liver failure: results of a comparative 1H-NMR spectroscopy and biochemical investigation. Hepatology 12:281–290Google Scholar
  12. Butterworth RF (1995) Hepatic encephalopathy. Neurologist 1:95–104Google Scholar
  13. Butterworth RF (1996) Taurine in hepatic encephalopathy. Adv Exp Med Biol 403:601–606PubMedGoogle Scholar
  14. Butterworth RF (2000) Complication of cirrhosis. III. Hepatic encephalopathy. J Hepatol 32:171–180PubMedCrossRefGoogle Scholar
  15. Chalasani N, Gitlin N (1997) Subclinical hepatic encephalopathy: How best to diagnose? Am J Gastroent 92:905–906PubMedGoogle Scholar
  16. Chih CP, Roberts EL Jr (2003) Energy substrates for neurons during neural activity: a critical review of the astrocyte-neuron lactate shuttle hypothesis. J Cereb Blood Flow Metab 23:1263–1281PubMedCrossRefGoogle Scholar
  17. Clarke DD, Sokoloff L (1999) Circulation and energy metabolism of the brain. In: Siegel GJ, Agranoff BW et al (eds) Basic neurochemistry. Lippincott-Raven, Philadelphia, pp 637–669Google Scholar
  18. Dhiman RK, Chawla YK (2009) Minimal hepatic encephalopathy. Indian J Gastroenterol 28:5–16PubMedCrossRefGoogle Scholar
  19. Duyn JH, Gillen J, Sobering G, van Zijl PC, Moonen CTW (1993) Multisection proton MR spectrosocopic imaging of the brain. Radiology 188:277–282PubMedGoogle Scholar
  20. Evanochko WT, Sakal TT, Ng TC, Krishnaa NR, Kimc HD, Zeidlerc RB, Ghantad VK, Brockmane RW, Schifferf LM, Braunschweigerf PG, Glicksona JD (1984) NMR study of in vivo RIF-1 tumors. Analysis of perchloric acid extracts and identification of 1H, 31P and 13C resonances. Biochim Biophys Acta 805:104–116PubMedCrossRefGoogle Scholar
  21. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT (2002) Hepatic encephalopathy–definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716–721PubMedCrossRefGoogle Scholar
  22. Foerster BR, Conklin LS, Petrou M, Barker PB, Schwarz KB (2009) Minimal hepatic encephalopathy in children: evaluation with proton MR spectroscopy. AJNR Am J Neuroradiol 30:1610–1613PubMedCrossRefGoogle Scholar
  23. Fraser CL, Arieff AI (1985) Hepatic encephalopathy. New Eng J Med 313:865–873PubMedCrossRefGoogle Scholar
  24. Frias-Martinez E, Rajakumar N, Liu X, Singhal A, Banakar S, Lipnick S, Verma G, Ramadan S, Kumar A, Thomas MA (2008) ProFit-based Quantitation of Cerebral Metabolites using 2D L-COSY at 3 T Magnetic Resonance. Proc Intl Soc Mag Reson Med 16: 691, Toronto, CanadaGoogle Scholar
  25. Gilberstadt SJ, Gilberstadt H, Zieve L, Buegel B, Collier RO Jr, McClain CJ (1980) Psychomotor performance defects in cirrhotic patients without overt encephalopathy. Arch Intern Med 140:519–521PubMedCrossRefGoogle Scholar
  26. Gitlin N (1996) Hepatic encephalopathy. In: Zorkin D, Boyer TD (eds) Hepatology. Saunders, Philadelphia, pp 605–617Google Scholar
  27. Govindaraju V, Young K, Maudsley AA (2000) Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 13:129–153PubMedCrossRefGoogle Scholar
  28. Griffiths JR, Cady E, Edwards RHT, McCready VR, Wilkie DR, Wiltshaw E (1983) 31P-NMR studies of a human tumour in situ. Lancet 1:1435–1436PubMedCrossRefGoogle Scholar
  29. Gruetter R, Novotny EJ, Boulware SD, Mason GF, Rothman DL, Shulman GI, Prichard JW, Shulman RG (1994) Localized 13C NMR spectroscopy in the human brain of amino acid labeling from D-[1-13C]glucose. J Neurochem 63:1377–1385PubMedCrossRefGoogle Scholar
  30. Haase A, Frahm J, Haenicke W, Matthaei D (1985) 1H NMR chemical-shift selective (CHESS) imaging. Phys Med Biol 30:341–344PubMedCrossRefGoogle Scholar
  31. Heaton RK, Grant I, Matthews CG (1991) Comprehensive norms for an expanded Halstead-Reitan battery: demographic corrections, research findings, and clinical applications. Psychological Assessment Resources, OdessaGoogle Scholar
  32. Hilbe JM (2009) Logistic regression models. Chapman & Hall/CRC PressGoogle Scholar
  33. Hilgier W, Law RO, Zielinska M (2000) Taurine, glutamine, glutamate, and aspartate content and efflux, cell volume of cerebrocortical minislices of rats with hepatic encephalopathy. Adv Exp Med Biol 483:305–312PubMedCrossRefGoogle Scholar
  34. Hosmer DW, Lemeshow S (1995) Applied Logistic Regression. John Wiley and Sons, Inc Menard, ScottGoogle Scholar
  35. Kaibara T, Tyson RL, Sutherland GR (1998) Human cerebral neoplasms studied using MR spectroscopy: a review. Biochem Cell Biol 76:477–486PubMedCrossRefGoogle Scholar
  36. Klein J, Gonzalez R, Koppen A, Loffelholz K (1993) Free choline and choline metabolites in rat brain and body fluids: sensitive determination and implications for choline supply to the brain. Neurochem Int 22:293–300PubMedCrossRefGoogle Scholar
  37. Koc H, Mar M, Ranasinghe A, Swenberg JA, Zeisel SH (2002) Quantitation of Choline and its Metabolites in Tissues and Foods by Liquid Chromatography/Electrospray Ionization-Isotope Dilution Mass Spectrometry. Analytical Chemistry 74:4734–4740PubMedCrossRefGoogle Scholar
  38. Kreis R, Ross BD, Farrow NA, Ackerman Z (1992) Metabolic disorders of the brain in chronic hepatic encephalopathy detected with H-1 MR spectroscopy. Radiology 182:19–27PubMedGoogle Scholar
  39. Larzelere RE, Mulak SA (1977) Single-sample tests for many correlations. Psychol Bull 84:557–569CrossRefGoogle Scholar
  40. Lavoie J, Giguere JF, Layrargues GP, Butterworth RF (1987) Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. J Neurochem 49:692–697PubMedCrossRefGoogle Scholar
  41. Leybaert L (2005) Neurobarrier coupling in the brain: a partner of neurovascular and neurometabolic coupling? J Cereb Blood Flow Metab 25:2–16PubMedGoogle Scholar
  42. Lezak MD (1995) Neuropsychological assessment. Oxford University Press, New York, pp 333–685Google Scholar
  43. Lockwood AH (2000) “What’s in a name?” Improving the care of cirrhotics. J Hepatol 32:859–861PubMedCrossRefGoogle Scholar
  44. Lockwood AH, Yap EWH, Wong WH (1991a) Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cerebral Blood Flow Metabol 11:337–341CrossRefGoogle Scholar
  45. Lockwood AH, Yap EWH, Rhodes HM, Wong WH (1991b) Altered cerebral blood flow and glucose metabolism in patients with liver disease and minimal encephalopathy. J Cerebral Blood Flow Metabol 11:331–336CrossRefGoogle Scholar
  46. Loening NM, Chamberlin AM, Zepeda AG, Gonzalez RG, Cheng LL (2005) Quantification of phosphocholine and glycerophosphocholine with 31P edited 1H NMR spectroscopy. NMR in Biomedicine 18:413–420PubMedCrossRefGoogle Scholar
  47. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497PubMedCrossRefGoogle Scholar
  48. McCrea M, Cordoba I, Vessey G, Blei AT, Randolph C (1996) Neuropsychological characterization and detection of subclinical hepatic encephalopathy. Arch Neurol 53:758–763PubMedGoogle Scholar
  49. McPhail MJ, Taylor-Robinson SD (2010) The role of magnetic resonance imaging and spectroscopy in hepatic encephalopathy. Metab Brain Dis 25:65–72PubMedCrossRefGoogle Scholar
  50. Miller BL, Chang L, Booth R, Ernst T, Cornford M, Nikas D, McBride D, Jenden DJ (1996) In Vivo 1H MRS Choline: Correlation with In Vitro Chemistry/Histology. Life Sciences 58:1929–1935PubMedCrossRefGoogle Scholar
  51. Mullen KD (2007) Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy. Aliment Pharmacol Ther 25:11–16PubMedCrossRefGoogle Scholar
  52. Ogg RJ, Kingsley PB, Taylor JS (1994) WET, a T1- and B1-insensitive water-suppression method for in vivo localized 1H NMR spectroscopy. J Magn Reson B 104:1–10PubMedCrossRefGoogle Scholar
  53. Patel N, Forton DM, Coutts GA, Thomas HC, Taylor-Robinson SD (2000) Intracellular pH measurements of the whole head and the basal ganglia in chronic liver disease: a phosphorus-31 MR spectroscopy study. Metab Brain Dis 15:223–240PubMedGoogle Scholar
  54. Pardridge WM, Cornford EM, Braun LD, Oldendorf WH (1979) Transport of choline and choline analogues through the blood-brain barrier. In: Barbeau A, Growdon JH, Wurtman RJ (eds) Nutrition and the Brain. Raven, New York, pp 25–33Google Scholar
  55. Pellerin L, Magistretti PJ (1997) Glutamate uptake stimulates Na+, K+-ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabian. J Neurochem 69:2132–2137PubMedCrossRefGoogle Scholar
  56. Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679PubMedCrossRefGoogle Scholar
  57. Romero-Gómez M (2007) Critical flicker frequency: it is time to break down barriers surrounding minimal hepatic encephalopathy. J Hepatol 47:10–11PubMedCrossRefGoogle Scholar
  58. Romero-Gómez M, Córdoba J, Jover R, del Olmo JA, Ramírez M, Rey R, de Madaria E, Montoliu C, Nuñez D, Flavia M, Compañy L, Rodrigo JM, Felipo V (2007) Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 45:879–885PubMedCrossRefGoogle Scholar
  59. Ross BD, Danielsen ER, Bluml S (1996) Proton magnetic resonance spectroscopy: The new gold standard for diagnosis of clinical and subclinical hepatic encephalopathy? Digest Dis 14:30–39CrossRefGoogle Scholar
  60. Ross BD, Jacobson S, Villamil F, Korula J, Kreis R, Ernst T, Shonk T, Moats RA (1994) Subclinical hepatic encephalopathy: proton MR spectroscopic abnormalities. Radiology 193:457–463PubMedGoogle Scholar
  61. Saxena N, Bhatia M, Joshi YK, Garg PK, Dwivedi SN, Tandon RK (2002) Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and prediction of overt encephalopathy. Liver 22:190–197PubMedCrossRefGoogle Scholar
  62. Schomerus H, Hamster W (1998) Neuropsychological aspects of portalsystemic encephalopathy. Metab Brain Dis 13:361–377PubMedCrossRefGoogle Scholar
  63. Schomerus H, Hamster W, Blunck H, Reinhard U, Mayer K, Dolle W (1981) Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive. Dig Dis Sci 26:622–630PubMedCrossRefGoogle Scholar
  64. Schulte RF, Boesiger P (2006) ProFit: two-dimensional prior-knowledge fitting of J-resolved spectra. NMR Biomed 19:255–263PubMedCrossRefGoogle Scholar
  65. Singhal A, Nagarajan R, Hinkin CH, Kumar R, Sayre J, Elderkin-Thompson V, Huda A, Gupta RK, Han SH, Thomas MA (2010) Two-dimensional MR spectroscopy of minimal hepatic encephalopathy and neuropsychological correlates in vivo. J Magn Reson Imaging 32:35–43PubMedCrossRefGoogle Scholar
  66. Smith SA, Levante TO, Meier BH, Ernst RR (1994) Computer-simulations in magnetic-resonance-an object-oriented programming approach. J Magn Reson A 106:75–105CrossRefGoogle Scholar
  67. Solivera J, Cerdan S, Pascual JM, Barrios L, Roda JM (2009) Assessment of 31P-NMR analysis of phospholipid profiles for potential differential diagnosis of human cerebral tumors. NMR in Biomedicine 22:663–674PubMedCrossRefGoogle Scholar
  68. Stewart CA, Smith GE (2007) Minimal hepatic encephalopathy. Nat Clin Pract Gastroenterol Hepatol 4:677–685PubMedCrossRefGoogle Scholar
  69. Tarter RE, Hegedus AM, Van Thiel DH, Schade RR, Gavaler JS, Starzl TE (1984) Nonalcoholic cirrhosis associated with neuropsychological dysfunction in the absence of overt evidence of hepatic encephalopathy. Gastroenterology 86:1421–1427PubMedGoogle Scholar
  70. Taylor-Robinson SD, Sargentoni J, Mallalieu RJ, Bell JD, Bryant DJ, Coutts GA, Morgan MY (1994) Cerebral phosphorus-31 magnetic resonance spectroscopy in patients with chronic hepatic encephalopathy. Hepatology 20:1173–1178PubMedCrossRefGoogle Scholar
  71. Taylor-Robinson SD, Buckley C, Changani KK, Hodgson HJ, Bell JD (1999) Cerebral proton and phosphorus-31 magnetic resonance spectroscopy in patients with subclinical hepatic encephalopathy. Liver 19:389–398PubMedCrossRefGoogle Scholar
  72. Thomas MA, Yue K, Binesh N, Davanzo P, Kumar A, Siegel B, Frye M, Curran J, Lufkin R, Martin P, Guze B (2001) Localized two-dimensional shift correlated MR spectroscopy of human brain. Magn Reson Med 46:58–67PubMedCrossRefGoogle Scholar
  73. Vaquero J, Butterworth RF (2006) The brain glutamate system in liver failure. J Neurochem 98:661–669PubMedCrossRefGoogle Scholar
  74. Wang YM (2004) The definition, nomenclature and diagnosis of hepatic encephalopathy. Zhonghua Gan Zang Bing Za Zhi 12:305–306PubMedGoogle Scholar
  75. Weissenborn K, Ahl B, Fischer-Wasels D, van den Hoff J, Hecker H, Burchert W, Köstler H (2007) Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy. Gut 56:1736–1742PubMedCrossRefGoogle Scholar
  76. Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H (2001) Neuropsychological characterization of hepatic encephalopathy. J Hepatol 34:768–773PubMedCrossRefGoogle Scholar
  77. Zimmerman C, Winnefeld K, Streck S, Roskosb M, Haberla RL (2004) Antioxidant status in acute stroke patients and patients at stroke risk. Eur Neurol 51:157–161CrossRefGoogle Scholar
  78. Zwingmann C, Chaturet N, Leibiritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [H-C] nuclear magnetic resonance study. Hepatology 37:420–428PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Manoj K. Sarma
    • 1
  • Amir Huda
    • 1
    • 2
  • Rajakumar Nagarajan
    • 1
  • Charles H. Hinkin
    • 3
    • 4
  • Neil Wilson
    • 1
  • Rakesh K. Gupta
    • 5
  • Enrique Frias-Martinez
    • 1
  • James Sayre
    • 1
  • Barry Guze
    • 3
  • Steven-Huy Han
    • 6
  • M. Albert Thomas
    • 1
    • 3
  1. 1.Department of Radiological Sciences, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of PhysicsCalifornia State UniversityFresnoUSA
  3. 3.Department of Psychiatry, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  4. 4.VA Greater Los Angeles Healthcare SystemLos AngelesUSA
  5. 5.Department of RadiologySanjay Gandhi Post-Graduate Institute of Medical SciencesLucknowIndia
  6. 6.Department of Hepatology, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA

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