Skip to main content

Advertisement

SpringerLink
Log in

In vivo studies of brain metabolism in animal models of Hepatic Encephalopathy using 1H Magnetic Resonance Spectroscopy

  • Original Paper
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Hepatic encephalopathy (HE) is a common and severe neuropsychiatric complication present in acute and chronic liver disease. The unique advantages of high field 1H MRS provide a method for assessing pathogenic mechanism, diagnosis and monitoring of HE, as well as for treatment assessment or recovery after liver transplantation, in a reproducible and reliable non-invasive way. The purpose of the present review is to present some new features of in vivo proton Magnetic Resonance Spectroscopy (1H MRS) at high magnetic fields combined with some basic requirements for reliable metabolic profiling. Finally, in vivo applications of 1H MRS in different HE animal models are presented.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Albrecht J, Norenberg MD (2006) Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44(4):788–794

    Article  PubMed  CAS  Google Scholar 

  • Bates TE, Williams SR, Kauppinen RA, Gadian DG (1989) Observation of cerebral metabolites in an animal-model of acute liver-failure invivo - a H-1 and P-31 nuclear magnetic-resonance study. J Neurochem 53(1):102–110

    Article  PubMed  CAS  Google Scholar 

  • Berl S, Takagaki G, Clarke DD, Waelsch H (1962) Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver. J Biol Chem 237:2562–2569

    PubMed  CAS  Google Scholar 

  • Bosman DK, Deutz NE, De Graaf AA, van den Hulst RW, Van Eijk HM, Bovee WM, Maas MA, Jorning 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(2):281–290

    Article  PubMed  CAS  Google Scholar 

  • Braissant O, McLin VA, Cudalbu C (2012) Ammonia toxicity to the brain. J Inherit Metab Dis Oct 30. [Epub ahead of print]

  • Brand A, Richter-Landsberg C, Leibfritz D (1993) Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 15(3–5):289–298

    Article  PubMed  CAS  Google Scholar 

  • Brusilow SW, Traystman R (1986) Hepatic encephalopathy. N Engl J Med 314(12):786–787, author reply 787

    PubMed  CAS  Google Scholar 

  • Brusilow SW, Koehler RC, Traystman RJ, Cooper AJ (2010) Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy. Neurotherapeutics 7(4):452–470

    Article  PubMed  CAS  Google Scholar 

  • Butterworth RF (2003) Pathogenesis of hepatic encephalopathy: new insights from neuroimaging and molecular studies. J Hepatol 39(2):278–285

    Article  PubMed  Google Scholar 

  • Cagnon L, Braissant O (2007) Hyperammonemia-induced toxicity for the developing central nervous system. Brain Res Rev 56(1):183–197

    Article  PubMed  CAS  Google Scholar 

  • Caudle SE, Katzenstein JM, Karpen SJ, McLin VA (2010) Language and motor skills are impaired in infants with biliary atresia before transplantation. J Pediatr 156(6):936–940, 940 e931

    Article  PubMed  Google Scholar 

  • Cauli O, Lopez-Larrubia P, Rodrigues TB, Cerdan S, Felipo V (2007) Magnetic resonance analysis of the effects of acute ammonia intoxication on rat brain. Role of NMDA receptors. J Neurochem 103(4):1334–1343

    Article  PubMed  CAS  Google Scholar 

  • Cauli O, Lopez-Larrubia P, Rodrigo R, Agusti A, Boix J, Nieto-Charques L, Cerdan S, Felipo V (2011) Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats. Gastroenterology 140(2):638–645

    Article  PubMed  CAS  Google Scholar 

  • Chatauret N, Zwingmann C, Rose C, Leibfritz D, Butterworth RF (2003) Effects of hypothermia on brain glucose metabolism in acute liver failure: a H/C-nuclear magnetic resonance study. Gastroenterology 125(3):815–824

    Article  PubMed  CAS  Google Scholar 

  • Chavarria L, Oria M, Romero-Gimenez J, Alonso J, Lope-Piedrafita S, Cordoba J (2010) Diffusion tensor imaging supports the cytotoxic origin of brain edema in a rat model of acute liver failure. Gastroenterology 138(4):1566–1573

    Article  PubMed  CAS  Google Scholar 

  • Cooper AJ (2011) 13 N as a tracer for studying glutamate metabolism. Neurochem Int 59(4):456–464

    Article  PubMed  CAS  Google Scholar 

  • Cooper AJ (2012) The role of glutamine synthetase and glutamate dehydrogenase in cerebral ammonia homeostasis. Neurochem Res 37(11):2439–2455

    Article  PubMed  CAS  Google Scholar 

  • Cooper AJ, Plum F (1987) Biochemistry and physiology of brain ammonia. Physiol Rev 67(2):440–519

    PubMed  CAS  Google Scholar 

  • Cordoba J (1996) Glutamine, myo-inositol, and brain edema in acute liver failure. Hepatology 23(5):1291–1292

    Article  PubMed  CAS  Google Scholar 

  • Cordoba J, Gottstein J, Blei AT (1996) Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema. Hepatology 24(4):919–923. doi:10.1002/hep.510240427

    PubMed  CAS  Google Scholar 

  • Cordoba J, Gottstein J, Blei AT (1998) Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis. J Hepatol 29(4):589–594

    Article  PubMed  CAS  Google Scholar 

  • Cordoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L, Vargas V, Margarit C, Kulisewsky J, Esteban R, Guardia J (2001) The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation. J Hepatol 35(5):598–604

    Article  PubMed  CAS  Google Scholar 

  • Cordoba J, Sanpedro F, Alonso J, Rovira A (2002) 1H magnetic resonance in the study of hepatic encephalopathy in humans. Metab Brain Dis 17(4):415–429

    Article  PubMed  CAS  Google Scholar 

  • Cudalbu C, Cavassila S, Rabeson H, van Ormondt D, Graveron-Demilly D (2008) Influence of measured and simulated basis sets on metabolite concentration estimates. NMR Biomed 21(6):627–636

    Article  PubMed  CAS  Google Scholar 

  • Cudalbu C, Mlynarik V, Xin L, Gruetter R (2009) Comparison of T1 relaxation times of the neurochemical profile in rat brain at 9.4 tesla and 14.1 tesla. Magn Reson Med 62(4):862–867

    Article  PubMed  CAS  Google Scholar 

  • Cudalbu C, Mlynárik V, Lanz B, Frenkel H, Costers N, Gruetter R (2010) Imaging glutamine synthesis rates in the hyperammonemic rat brain. In: Proc Intl Soc Mag Reson Med 18:3324

  • Cudalbu C, Braissant O, Lepore M, Gruetter R, McLin VA (2012a) Brain osmolytes and brain edema in a rat model of chronic liver failure: in vivo longitudinal 1H spectroscopic imaging and diffusion tensor imaging studies at 9.4T. 15th ISHEN Symposium O7

  • Cudalbu C, Lanz B, Duarte JM, Morgenthaler FD, Pilloud Y, Mlynarik V, Gruetter R (2012b) Cerebral glutamine metabolism under hyperammonemia determined in vivo by localized (1)H and (15)N NMR spectroscopy. J Cereb Blood Flow Metab 32(4):696–708

    Article  PubMed  CAS  Google Scholar 

  • Cudalbu C, Mlynarik V, Gruetter R (2012c) Handling macromolecule signals in the quantification of the neurochemical profile. J Alzheimers Dis 31:S101–S115

    PubMed  Google Scholar 

  • de Graaf RA, Brown PB, McIntyre S, Nixon TW, Behar KL, Rothman DL (2006) High magnetic field water and metabolite proton T1 and T2 relaxation in rat brain in vivo. Magn Reson Med 56(2):386–394

    Article  PubMed  Google Scholar 

  • Desjardins P, Du T, Jiang W, Peng L, Butterworth RF (2012) Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined. Neurochem Int 60(7):690–696

    Article  PubMed  CAS  Google Scholar 

  • Felipo V, Butterworth RF (2002) Neurobiology of ammonia. Prog Neurobiol 67(4):259–279

    Article  PubMed  CAS  Google Scholar 

  • Fitzpatrick SM, Hetherington HP, Behar KL, Shulman RG (1989) Effects of acute hyperammonemia on cerebral amino acid metabolism and pHi in vivo, measured by 1H and 31P nuclear magnetic resonance. J Neurochem 52(3):741–749

    Article  PubMed  CAS  Google Scholar 

  • Haussinger D, Kircheis G, Fischer R, Schliess F, vom Dahl S (2000) Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol 32(6):1035–1038

    Article  PubMed  CAS  Google Scholar 

  • Kreis R, Farrow N, Ross BD (1991) Localized 1H NMR spectroscopy in patients with chronic hepatic encephalopathy. Analysis of changes in cerebral glutamine, choline and inositols. NMR Biomed 4(2):109–116

    Article  PubMed  CAS  Google Scholar 

  • 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(1):19–27

    PubMed  CAS  Google Scholar 

  • Leke R, Bak LK, Anker M, Melo TM, Sorensen M, Keiding S, Vilstrup H, Ott P, Portela LV, Sonnewald U, Schousboe A, Waagepetersen HS (2011) Detoxification of ammonia in mouse cortical GABAergic cell cultures increases neuronal oxidative metabolism and reveals an emerging role for release of glucose-derived alanine. Neurotox Res 19(3):496–510

    Article  PubMed  CAS  Google Scholar 

  • McPhail MJ, Taylor-Robinson SD (2010) The role of magnetic resonance imaging and spectroscopy in hepatic encephalopathy. Metab Brain Dis 25(1):65–72

    Article  PubMed  Google Scholar 

  • Mekle R, Mlynarik V, Gambarota G, Hergt M, Krueger G, Gruetter R (2009) MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3 T and 7 T. Magn Reson Med 61(6):1279–1285

    Article  PubMed  CAS  Google Scholar 

  • Mlynarik V, Cudalbu C, Xin L, Gruetter R (2008a) 1H NMR spectroscopy of rat brain in vivo at 14.1Tesla: improvements in quantification of the neurochemical profile. J Magn Reson 194(2):163–168

    Article  PubMed  CAS  Google Scholar 

  • Mlynarik V, Kohler I, Gambarota G, Vaslin A, Clarke PG, Gruetter R (2008b) Quantitative proton spectroscopic imaging of the neurochemical profile in rat brain with microliter resolution at ultra-short echo times. Magn Reson Med 59(1):52–58

    Article  PubMed  CAS  Google Scholar 

  • Munoz SJ (2008) Hepatic encephalopathy. Med Clin North Am 92(4):795–812, viii

    Article  PubMed  CAS  Google Scholar 

  • Norenberg MD (1979) Distribution of glutamine synthetase in the rat central nervous system. J Histochem Cytochem 27(3):756–762

    Article  PubMed  CAS  Google Scholar 

  • Norenberg MD, Rama Rao KV, Jayakumar AR (2009) Signaling factors in the mechanism of ammonia neurotoxicity. Metab Brain Dis 24(1):103–117

    Article  PubMed  CAS  Google Scholar 

  • Nyberg SL, Cerra FB, Gruetter R (1998) Brain lactate by magnetic resonance spectroscopy during fulminant hepatic failure in the dog. Liver Transpl Surg 4(2):158–165

    Article  PubMed  CAS  Google Scholar 

  • Rama Rao KV, Jayakumar AR, Norenberg MD (2012) Glutamine in the pathogenesis of acute hepatic encephalopathy. Neurochem Int 61(4):575–580

    Article  PubMed  CAS  Google Scholar 

  • 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(2):457–463

    PubMed  CAS  Google Scholar 

  • Rovira A, Alonso J, Cordoba J (2008) MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol 29(9):1612–1621

    Article  PubMed  CAS  Google Scholar 

  • Shen J, Sibson NR, Cline G, Behar KL, Rothman DL, Shulman RG (1998) 15 N-NMR spectroscopy studies of ammonia transport and glutamine synthesis in the hyperammonemic rat brain. Dev Neurosci 20(4–5):434–443

    Article  PubMed  CAS  Google Scholar 

  • Spahr L, Burkhard PR, Grotzsch H, Hadengue A (2002) Clinical significance of basal ganglia alterations at brain MRI and 1H MRS in cirrhosis and role in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 17(4):399–413

    Article  PubMed  CAS  Google Scholar 

  • Tkac I, Gruetter R (2005) Methodology of H NMR spectroscopy of the human brain at very high magnetic fields. Appl Magn Reson 29(1):139–157

    Article  PubMed  CAS  Google Scholar 

  • Tkac I, Oz G, Adriany G, Ugurbil K, Gruetter R (2009) In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4 T vs. 7 T. Magn Reson Med 62(4):868–879

    Article  PubMed  CAS  Google Scholar 

  • Urenjak J, Williams SR, Gadian DG, Noble M (1993) Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 13(3):981–989

    PubMed  CAS  Google Scholar 

  • Williams S (1999) Cerebral amino acids studied by nuclear magnetic resonance spectroscopy in vivo. Prog Nucl Magn Reson Spectrosc 34(3–4):301–326

    Article  CAS  Google Scholar 

  • Zwingmann C (2007) The anaplerotic flux and ammonia detoxification in hepatic encephalopathy. Metab Brain Dis 22(3–4):235–249

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by Centre d’Imagerie BioMédicale (CIBM) of the UNIL, UNIGE, HUG, CHUV, EPFL, the Leenaards and Jeantet Foundations. The author thanks Dr O. Braissant (Service of Biomedicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland) and Dr V. McLin (Pediatric Gastroenterology Unit, Department of Child and Adolescent, University Hospitals of Geneva (HUG), Geneva, Switzerland) the main collaborators on the project briefly presented in the present review and Drs V. Mlynarik and B. Lanz (Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland) for reviewing the manuscript.

Author information

Authors and Affiliations

  1. Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratory for Functional and Metabolic Imaging (LIFMET), Station 6, CH F1 602 (Bâtiment CH), 1015, Lausanne, Switzerland

    Cristina Cudalbu

Authors
  1. Cristina Cudalbu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cristina Cudalbu.

Additional information

Sources of support

Supported by Centre d’Imagerie BioMédicale (CIBM) of the UNIL, UNIGE, HUG, CHUV, EPFL; the Leenaards and Jeantet Foundations.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cudalbu, C. In vivo studies of brain metabolism in animal models of Hepatic Encephalopathy using 1H Magnetic Resonance Spectroscopy. Metab Brain Dis 28, 167–174 (2013). https://doi.org/10.1007/s11011-012-9368-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-012-9368-9

Keywords

Search

Navigation