Skip to main content

Advertisement

SpringerLink
Log in

Reduced glutamate neurotransmission in patients with Alzheimer's disease–an in vivo 13C magnetic resonance spectroscopy study

  • Research Article
  • Published:
Magnetic Resonance Materials in Physics, Biology and Medicine Aims and scope Submit manuscript

Abstract

Cognitive impairment in Alzheimer's disease (AD) is not fully explained. PET indicates reduced cerebral metabolic rate for glucose. Since glutamate neurotransmission (GNT) consumes more than 80% of the ATP generated from metabolism, a pilot study was carried out to determine the neuronal tricarboxylic acid cycle (TCA) based on the hypothesis that reduced GNT could contribute to cognitive impairment in AD.

Three AD patients with cognitive impairment (mini-mental state exam: 24 vs 30, P<0.05) and significant reduction in both N-acetyl aspartate (NAA)/Creatine (Cr) (P<0.009) and NAA/myo-inositol (mI) ratio (P<0.01), and three age-matched controls each received 0.014–0.016 g/kg/min 99%1–13C glucose IV. Quantitative 1H and proton-decoupled 13C MR brain spectra were acquired from combined posterior-parietal white matter and posterior-cingulate gray matter every 5 min for 140 min.

13C magnetic resonance spectroscopy (MRS) measures of glucose oxidation and neuronal TCA rate, including prolonged time to 13C enrichment of glutamate (Glu2) (P<0.004) and bicarbonate (HCO3) (P<0.03) as well as reduced relative enrichment of Glu2/Glu4 between 60 and 100 min (P<0.04), were significantly different in AD patients vs. controls. 13C measures of GNT, glutamine (Gln)2/Glu2 (P<0.02) and rates of glutamate enrichment (Glu2/glucose: 0.34 vs 0.86, P=ns and Glu4/glucose 0.26 vs 0.83, P=ns), were also reduced.

13C MRS measures of neuronal TCA cycle, glucose oxidation and GNT were significantly correlated with measures of neuronal integrity: NAA/Cr, [NAA] and mI/NAA as determined by 1H MRS (R 2=0.73–0.95; P<0.05–0.01), suggesting that impairment of GNT may be a contributing factor in the cognitive impairment characteristic of AD.

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.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3. A
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.
Fig. 8.

Similar content being viewed by others

References

  1. Alzheimer's Association: general statistics and demographics. http://www.alz.org/hc/overview/stats.htm

  2. Alzheimer A, Stelzmann RA, Schnitzlein HN and Murtagh F (1995) An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkrankung der Hirnrinde". Clin Anat 8:429–431

    Google Scholar 

  3. Morris RG (1991) The nature of memory impairment in Alzheimer-type dementia. In: Weinman J, Hunter J (eds) Memory: neurochemical and abnormal perspectives. Harwood, London, pp 56–59

  4. Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, Small GW, Miller B, Stevens JC (2001) Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 56:1143–1153

  5. de Jager CA, Milwain E, Budge M (2002) Early detection of isolated memory deficits in the elderly: the need for more sensitive neuropsychological tests. Psychol Med 32:483–491

    Google Scholar 

  6. Cummings JL, Cole G (2002) Alzheimer disease. JAMA 287:2335–2338

    Google Scholar 

  7. Braak H, Braak E (1991) Neuropathological staging of Alzheimer related changes. Acta Neuropathol 82:239–259

    Google Scholar 

  8. Gosche KM, Mortimer JA, Smith CD, Markesbery WR, Snowdon DA (2002) Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study. Neurology 58:1476–1482

    Google Scholar 

  9. Jack Jr. CR, Petersen RC, Xu YC (1999) Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 52:1397–1403

  10. Holmes C (2002) Genotype and phenotype in Alzheimer's disease. Br J Psychiatry 180:131–134

    Google Scholar 

  11. Isacson O, Seo H, Lin L, Albeck D, Granhom AC (2002) Alzheimer's disease and Down's syndrome: Roles of APP, trophic factors and ACh. Trends Neurosci 25:79–84

    Google Scholar 

  12. Schuff N, Amend D, Ezekiel F, Steinman SK, Tanabe J, Norman D, Jagust W, Kramer JH, Mastrianni JA, Fein G, Weiner MW (1997) Changes of hippocampal N-acetyl aspartate and volume in Alzheimer's disease. A proton MR spectroscopic imaging and MRI study. Neurology 49:1513–1521

    Google Scholar 

  13. Moffett JR, Namboodiri MA, Neale JH(1993) Enhanced carbodiimide fixation for immunohistochemistry: application to the comparative distributions of N-acetylaspartylglutamate and N-acetylaspartate immunoreactivities in rat brain. J Histochem Cytochem 41:559–570

    Google Scholar 

  14. Moats RA, Ernst T, Shonk TK, Ross BD (1994) Abnormal cerebral metabolite concentrations in patients with probable Alzheimer disease. Magn Reson Med 32:110–115

    Google Scholar 

  15. Kantarci K, Jack Jr. CR, Xu YC, Campeau NG, O'Brien PC, Smith GE, Ivnik RJ, Boeve BF, Kokmen E, Tangalos EG, Petersen RC (2000) Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: A 1H MRS study. Neurology 55:210–217

  16. Huang W, Alexander GE, Chang L, Shetty HU, Krasuski JS, Rapoport SI, Schapiro MB (2001) Brain metabolite concentration and dementia severity in Alzheimer's disease: a (1)H MRS study. Neurology 57:626–632

    Google Scholar 

  17. Shonk TK, Moats RA, Gifford P, Michaelis T, Mandigo JC, Izumi J, Ross BD (1995) Probable Alzheimer disease: diagnosis with proton MR spectroscopy. Radiology 195:65–72

    Google Scholar 

  18. Lin A, Sheih D, Shic F, Chien TY, Ross BD (2002) Validation of MRS in early diagnosis of Alzheimer's disease. J Geriatric Psychiatry Neurol p.176

  19. Ross BD, Bluml S, Cowan R, Danielsen E, Farrow N, Gruetter R (1997) In vivo magnetic resonance spectroscopy of human brain: The biophysical basis of dementia. Biophys Chem 68:161–172

    Google Scholar 

  20. Hattori N, Abe K, Sakoda S, Sawada T 2002 Proton MR spectroscopic study at 3 Tesla on glutamate/glutamine in Alzheimer's disease. Neuroreport 13:183–186

    Google Scholar 

  21. Antuono PG, Jones JL, Wang Y, Li SJ (2001) Decreased glutamate + glutamine in Alzheimer's disease detected in vivo with (1)H-MRS at 0.5 T. Neurology 56:737–742

    Google Scholar 

  22. Reinikainen KJ, Paljarvi L, Huuskonen M, Soininen H, Laakso M and Riekkinen PJ (1988) A post-mortem study of noradrenergic, serotonergic and GABAergic neurons in Alzheimer's disease. J Neurol Sci 84:101–116

    Google Scholar 

  23. Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38:357–366

    Google Scholar 

  24. Smith CD, Pettigrew LC, Avison MJ, Kirsch JE, Tinkhtman AJ, Schmitt FA, Wermeling DP, Wekstein DR, Markesberry WR (1995) Frontal lobe phosphorus metabolism and neuropsychological function in aging and in Alzheimer's disease. Ann Neurol 38:194–201

    Google Scholar 

  25. Bluml S, Danielsen ER, Ross BD (1996) Proton decoupled 31P MRS in Alzheimer disease. Proceedings, 4th International Society of Magnetic Resonance in Medicine, vol 1. New York, p. 304

  26. Ross BD, Bluml S, Cowan R, Danielsen E, Farrow N, Gruetter R, Tan J (1998) In vivo MRS spectroscopy of human dementia. Neuroimaging Clinics of North America. 8:1–14

  27. Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps ME (2001) Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 286:2120–2127

  28. Desgranges B, Baron JC, Lalevee C, Giffard B, Viader F, de La Sayette V, Eustache F (2002) The neural substrates of episodic memory impairment in Alzheimer's disease as revealed by FDG-PET: relationship to degree of deterioration. Brain 125:1116–1124

    Google Scholar 

  29. Schulman RJ (2001) Functional imaging studies: Linking mind and basic neuroscience. Am J Psychiatry 158:11–20

    Google Scholar 

  30. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on demand. Science 283:496–497

    Google Scholar 

  31. Attwell D, Laughlin SB (2001) An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 21:1135–1145

    Google Scholar 

  32. Beckmann N, Seelig J, Wick H (1990) Analysis of glycogen storage disease by in vivo 13C NMR: comparison of normal volunteers with a patient. Magn Reson Med 16:150–160

    Google Scholar 

  33. Mason GF, Rothman DL, Behar KL, Shulman RG (1992) NMR determination of the TCA cycle rate and α-ketoglutarate/glutamate exchange rate in rat brain. J Cereb Blood Flow Metab 12:434–447

    Google Scholar 

  34. Gruetter R, Seaquist ER, Kim S, Ugurbil K(1998) Localized in vivo 13C-NMR of glutamate metabolism in the human brain: Initial results at 4 Tesla. Dev Neurosci 20:380–388

    Google Scholar 

  35. Moreno A, Bluml S, Hwang J-H, Ross BD (2001) Alternative 1–13C glucose infusion protocols for clinical 13C MRS examinations of the brain. Magn Reson Med 46:36–48

    Google Scholar 

  36. Kreis R, Ernst T, Ross BD (1993) Absolute quantitation of water and metabolites in the human brain. Part II. Metabolite concentrations. J Magn Reson 102:9–19

    Google Scholar 

  37. Ernst T, Kreis R, Ross BD (1993) Absolute quantitation of water and metabolites in the human brain. I. Compartments and water. J Magn Reson 102:1–8

    Google Scholar 

  38. Bluml S, Hwang J-H, Moreno A, Ross BD (2000) Novel peak assignments of in vivo 13C MRS in human brain at 1.5 T. J Magn Reson 143:292–298

    Google Scholar 

  39. Adriany G, Gruetter R (1997) A half-volume coil for efficient proton decoupling in humans at 4 Tesla. J Magn Reson 125:178–184

    Google Scholar 

  40. Bluml S (1999) In vivo quantitation of cerebral metabolites concentration using natural abundance 13C MRS at 1.5 T. J Magn Reson 136:219–225

    Google Scholar 

  41. Shaka AJ, Keeler J, Frenkiel T and Freeman R. An improved sequence for broadband decoupling: WALTZ-16. J Magn Reson 198352:335–338

  42. Shaka AJ, Keeler J and Freeman R (1983) Evaluation of a new broadband decoupling sequence: WALTZ-16. J Magn Reson 53:313–340

    Google Scholar 

  43. Gruetter R, Adriany G, Merkle H and Anderson PM (1996) Broadband decoupled 1H-localized 13C MRS of the human brain at 4 Tesla. Magn Reson Med 36:659

    Google Scholar 

  44. Bluml S, Moreno-Torres A, Ross BD (2001) [1–13C] glucose MRS in chronic hepatic encephalopathy in man. Magn Reson Med 45:981–993

    Google Scholar 

  45. Shic F, Lin A, Ross BD (2002) Automated methods for analysis of large quantitites of13C MRS data in clinical studies. J Magn Reson (in press)

  46. Mason GF, Behar KL, Rothman DL, Shulman RG (1992) NMR determination of intracerebral glucose concentration and transport kinetics in rat brain. J Cereb Blood Flow Metab 12:448–455

    Google Scholar 

  47. Mason GF, Gruetter R, Rothman DL, Behar KL, Shulman RG, Novotny EJ (1995) Simultaneous determination of the rates of the TCA cycle, glucose utilization, a-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR. J Cereb Blood Flow Metab 15:12–25

    Google Scholar 

  48. Bluml S, Moreno A, Hwang J-H, Ross BD (2001) 1–13C glucose magnetic resonance spectroscopy of pediatric and adult brain disorders. NMR Biomed 14:19–32

    Google Scholar 

  49. Bluml S, Moreno-Torres A, Shic F, Nguy C-H, Ross BD 2002 Tricarboxylic acid cycle of glia in the in vivo human brain. NMR Biomed 15:1–5

    Google Scholar 

  50. Lebon V, Peterson K, Cline GW, et. al (2002) Astroglial contribution to brain energy metabolism in humans revealed by13C nuclear magnetic resonance spectroscopy: elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. J Neurosci 22:1523–1531

    Google Scholar 

  51. Lentner C (1982) In: Lentner C (ed) Introduction to statistics. Ciba-Geigy, Basel, p 49

  52. Moreno A, Ross BD, Bluml S (2001) Direct determination of the N-acetyl-L-aspartate synthesis rate in the human 13C MRS and [1–13C] glucose infusion. J Neurochem 77:347–350

    Google Scholar 

  53. Sibson NR, Dhankhar A, Mason GF, Rothman DL, Behar KL, Shulman RG (1998) Stoichiometric coupling between brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci USA 95:316–321

    Google Scholar 

  54. Gruetter R, Seaquist ER, Ugurbil K (2001) A mathematical model of compartmentalized neurotransmitter metabolism in the human brain. Am J Physiol Endocrinol Metab 281:E100-E112

    Google Scholar 

  55. Lewandowski ED, Hulbert C (1991) Dynamic changes in 13C NMR spectra of intact hearts under conditions of varied metabolite enrichment. Magn Reson Med 19:186–190

    Google Scholar 

  56. Janus C, Westaway D (2001) Transgenic mouse models of Alzheimer's disease. Physiol Behav 73:873–886

    Google Scholar 

  57. Anger WK (1991) Animal test systems to study behavioral dysfunctions of neurodegenerative disorders. Neurotoxicology 12:403–413

    Google Scholar 

  58. Robinson SR (2001) Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease. J Neurosci Res 66:972–980

    Google Scholar 

  59. Baslow M (2000) Functions of N-acetyl-l-aspartate and N-acetyl-l-aspartylglutamate in the vertebrate brain: role in glial cell-specific signaling. J Neurochem 75:453–459

    Google Scholar 

  60. Kanamori K, Ross BD (2001) The first in vivo observation of 13C-15 N coupling in mammalian brain. J Magn Reson 153:193–202

    Google Scholar 

Download references

Acknowledgements

A.P. Lin is grateful for a MR Research Fellowship at HMRI. The authors also thank Drs. Keiko Kanamori and Stefan Bluml for their expert discussion.

Author information

Authors and Affiliations

  1. Clinical Spectroscopy Unit, Huntington Medical Research Institutes, 660 S. Fair Oaks Avenue, Pasadena, CA , 91105, USA

    Alexander P. Lin & Brian D. Ross

  2. Rudi Schulte Research Institute, Santa Barbara, CA, USA

    Frederick Shic & Cathleen Enriquez

Authors
  1. Alexander P. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frederick Shic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cathleen Enriquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian D. Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander P. Lin.

Additional information

Submitted by Alexander P Lin, Winner, in partial fulfillment of the requirements of the Young Investigator Award Finalists, European Society of Magnetic Resonance in Medicine and Biology (ESMRMB), Cannes, France, 2002

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, A.P., Shic, F., Enriquez, C. et al. Reduced glutamate neurotransmission in patients with Alzheimer's disease–an in vivo 13C magnetic resonance spectroscopy study. MAGMA 16, 29–42 (2003). https://doi.org/10.1007/s10334-003-0004-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10334-003-0004-x

Keywords

Search

Navigation