Skip to main content

Advertisement

SpringerLink
Log in

Magnetic resonance spectroscopy in MELAS syndrome: correlation with CSF and plasma metabolite levels and change after glutamine supplementation

  • Advanced Neuroimaging
  • Published:
Neuroradiology Aims and scope Submit manuscript

Abstract

Purpose

MELAS syndrome is a genetic disorder caused by mitochondrial DNA mutations. We previously described that MELAS patients had increased CSF glutamate and decreased CSF glutamine levels and that oral glutamine supplementation restores these values. Proton magnetic resonance spectroscopy (1H-MRS) allows the in vivo evaluation of brain metabolism. We aimed to compare 1H-MRS of MELAS patients with controls, the 1H-MRS after glutamine supplementation in the MELAS group, and investigate the association between 1H-MRS and CSF lactate, glutamate, and glutamine levels.

Methods

We conducted an observational case–control study and an open-label, single-cohort study with single-voxel MRS (TE 144/35 ms). We assessed the brain metabolism changes in the prefrontal (PFC) and parieto-occipital) cortex (POC) after oral glutamine supplementation in MELAS patients. MR spectra were analyzed with jMRUI software.

Results

Nine patients with MELAS syndrome (35.8 ± 3.2 years) and nine sex- and age-matched controls were recruited. Lactate/creatine levels were increased in MELAS patients in both PFC and POC (0.40 ± 0.05 vs. 0, p < 0.001; 0.32 ± 0.03 vs. 0, p < 0.001, respectively). No differences were observed between groups in glutamate and glutamine (Glx/creatine), either in PFC (p = 0.930) or POC (p = 0.310). No differences were observed after glutamine supplementation. A positive correlation was found between CSF lactate and lactate/creatine only in POC (0.85, p = 0.003).

Conclusion

No significant metabolite changes were observed in the brains of MELAS patients after glutamine supplementation. While we found a positive correlation between lactate levels in CSF and 1H-MRS in MELAS patients, we could not monitor treatment response over short periods with this tool.

Trial registration

ClinicalTrials.gov Identifier: NCT04948138; initial release 24/06/2021; first patient enrolled on 1/07/2021. https://clinicaltrials.gov/ct2/show/NCT04948138

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

Similar content being viewed by others

Data availability

Data available on request from the authors.

References

  1. Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, DiMauro S, Rowland LP (1992) Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord 2:125–135

    Article  PubMed  CAS  Google Scholar 

  2. El-Hattab AW, Adesina AM, Jones J, Scaglia F (2015) MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab 116(1–2):4–12. https://doi.org/10.1016/j.ymgme.2015.06.004

    Article  PubMed  CAS  Google Scholar 

  3. Cheng W, Zhang Y, He L (2022) MRI Features of stroke-like episodes in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Front Neurol 9(13):843386. https://doi.org/10.3389/fneur.2022.843386

    Article  Google Scholar 

  4. Guerrero-Molina MP, Morales-Conejo M, Delmiro A et al (2022) Elevated glutamate and decreased glutamine levels in the cerebrospinal fluid of patients with MELAS syndrome. J Neurol 269(6):3238–3248. https://doi.org/10.1007/s00415-021-10942-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15(4):961–973. https://doi.org/10.1016/0896-6273(95)90186-8

    Article  PubMed  CAS  Google Scholar 

  6. Moore HL, Blain AP, Turnbull DM, Gorman GS (2020) Systematic review of cognitive deficits in adult mitochondrial disease. Eur J Neurol 27(1):3–17. https://doi.org/10.1111/ene.14068

    Article  PubMed  CAS  Google Scholar 

  7. Finsterer J (2008) Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). J Neurol Sci 272(1–2):20–33. https://doi.org/10.1016/j.jns.2008.05.011

    Article  PubMed  CAS  Google Scholar 

  8. González de la Aleja J, Ramos A, Mato-Abad V, Martínez-Salio A, Hernández-Tamames JA, Molina JA, Hernández-Gallego J, Alvarez-Linera J (2013) Higher glutamate to glutamine ratios in occipital regions in women with migraine during the interictal state. Headache. 53(2):365–75. https://doi.org/10.1111/head.12030

    Article  PubMed  Google Scholar 

  9. Zielman R, Wijnen JP, Webb A et al (2017) Cortical glutamate in migraine. Brain 140(7):1859–1871. https://doi.org/10.1093/brain/awx130

    Article  PubMed  Google Scholar 

  10. Çavus I, Romanyshyn JC, Kennard JT et al (2016) Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: microdialysis study of 79 patients at the yale epilepsy surgery program. Ann Neurol 80(1):35–45. https://doi.org/10.1002/ana.24673

    Article  PubMed  CAS  Google Scholar 

  11. Chan F, Lax NZ, Voss CM et al (2019) The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction. Brain 142(2):391–411. https://doi.org/10.1093/brain/awy320

    Article  PubMed  PubMed Central  Google Scholar 

  12. Guerrero-Molina MP, Morales-Conejo M, Delmiro A, et al (2022) High-dose oral glutamine supplementation reduces elevated glutamate levels in cerebrospinal fluid in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome [published online ahead of print, 2022 Nov 5]. Eur J Neurol. https://doi.org/10.1111/ene.15626. https://doi.org/10.1111/ene.15626

  13. Ito H, Mori K, Harada M et al (2008) Serial brain imaging analysis of stroke-like episodes in MELAS. Brain Dev 30(7):483–488. https://doi.org/10.1016/j.braindev.2008.01.003

    Article  PubMed  Google Scholar 

  14. Weiduschat N, Kaufmann P, Mao X, Engelstad KM, Hinton V, DiMauro S et al (2014) Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers. Neurology 82:798–805. https://doi.org/10.1212/WNL.0000000000000169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Lee HN, Yoon CS, Lee YM (2018) Correlation of serum biomarkers and magnetic resonance spectroscopy in monitoring disease progression in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes due to mtDNA A3243G mutation. Front Neurol 27(9):621. https://doi.org/10.3389/fneur.2018.00621

    Article  Google Scholar 

  16. Hovsepian DA, Galati A, Chong RA, Mazumder R, DeGiorgio CM, Mishra S, Yim C (2019) MELAS: Monitoring treatment with magnetic resonance spectroscopy. Acta Neurol Scand 139(1):82–85. https://doi.org/10.1111/ane.13027

    Article  PubMed  CAS  Google Scholar 

  17. Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP (1984) Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 16(4):481–488. https://doi.org/10.1002/ana.410160409

    Article  PubMed  CAS  Google Scholar 

  18. Naressi A, Couturier C, Devos JM et al (2001) Java-based graphical user interface for the MRUI quantitation package. MAGMA 12(2–3):141–152. https://doi.org/10.1007/BF02668096

    Article  PubMed  CAS  Google Scholar 

  19. Stefan D, Cesare FD, Andrasescu A, Popa E, Lazariev A, Vescovo E et al (2009) Quantitation of magnetic resonance spectroscopy signals: the jMRUI software package. Meas Sci Technol 20:104035

    Article  ADS  Google Scholar 

  20. Vanhamme L, van den Boogaart A, Van Huffel S (1997) Improved method for accurate and efficient quantification of MRS data with use of prior knowledge. J Magn Reson 129(1):35–43. https://doi.org/10.1006/jmre.1997.1244

    Article  ADS  PubMed  CAS  Google Scholar 

  21. Bernabeu A, Alfaro A, García M, Fernández E (2009) Proton magnetic resonance spectroscopy (1H-MRS) reveals the presence of elevated myo-inositol in the occipital cortex of blind subjects. Neuroimage 47(4):1172–1176. https://doi.org/10.1016/j.neuroimage.2009.04.080

    Article  PubMed  Google Scholar 

  22. Curi R, Lagranha CJ, Doi SQ et al (2005) Molecular mechanisms of glutamine action. J Cell Physiol. 204(2):392–401. https://doi.org/10.1002/jcp.20339

    Article  PubMed  CAS  Google Scholar 

  23. Chen Q, Kirk K, Shurubor YI et al (2018) Rewiring of glutamine metabolism is a bioenergetic adaptation of human cells with mitochondrial DNA mutations. Cell Metab 27(5):1007-1025.e5. https://doi.org/10.1016/j.cmet.2018.03.002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. McKenna MC (2007) The glutamate-glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85(15):3347–3358. https://doi.org/10.1002/jnr.21444

    Article  PubMed  CAS  Google Scholar 

  25. Takado Y, Sato N, Kanbe Y et al (2019) Association between brain and plasma glutamine levels in healthy young subjects investigated by MRS and LC/MS. Nutrients. 11(7):1649. https://doi.org/10.3390/nu11071649. (Published 2019 Jul 19)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Wilichowski E, Pouwels PJ, Frahm J, Hanefeld F (1999) Quantitative proton magnetic resonance spectroscopy of cerebral metabolic disturbances in patients with MELAS. Neuropediatrics 30(5):256–263. https://doi.org/10.1055/s-2007-973500

    Article  PubMed  CAS  Google Scholar 

  27. Möller HE, Kurlemann G, Pützler M, Wiedermann D, Hilbich T, Fiedler B (2005) Magnetic resonance spectroscopy in patients with MELAS. J Neurol Sci 229–230:131–139. https://doi.org/10.1016/j.jns.2004.11.014

    Article  PubMed  Google Scholar 

  28. Wang R, Hu B, Sun C, Geng D, Lin J, Li Y (2021) Metabolic abnormality in acute stroke-like lesion and its relationship with focal cerebral blood flow in patients with MELAS: evidence from proton MR spectroscopy and arterial spin labeling. Mitochondrion 59:276–282. https://doi.org/10.1016/j.mito.2021.06.012

    Article  PubMed  CAS  Google Scholar 

  29. Kamada K, Takeuchi F, Houkin K et al (2001) Reversible brain dysfunction in MELAS: MEG, and (1)H MRS analysis. J Neurol Neurosurg Psychiatry 70(5):675–678. https://doi.org/10.1136/jnnp.70.5.675

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Bianchi MC, Tosetti M, Battini R et al (2003) Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance. AJNR Am J Neuroradiol 24(10):1958–1966

    PubMed  PubMed Central  Google Scholar 

  31. Gramegna LL, Evangelisti S, Di Vito L et al (2021) Brain MRS correlates with mitochondrial dysfunction biomarkers in MELAS-associated mtDNA mutations. Ann Clin Transl Neurol 8(6):1200–1211. https://doi.org/10.1002/acn3.51329

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Arun P, Moffett JR, Namboodiri AM (2009) Evidence for mitochondrial and cytoplasmic N-acetylaspartate synthesis in SH-SY5Y neuroblastoma cells. Neurochem Int 55(4):219–225. https://doi.org/10.1016/j.neuint.2009.03.003

    Article  PubMed  CAS  Google Scholar 

  33. Clark JB (1998) N-Acetyl Aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 20:271–276. https://doi.org/10.1159/000017321

    Article  PubMed  CAS  Google Scholar 

  34. Liu Z, Zheng D, Wang X et al (2011) Apparent diffusion coefficients of metabolites in patients with MELAS using diffusion-weighted MR spectroscopy. AJNR Am J Neuroradiol 32(5):898–902. https://doi.org/10.3174/ajnr.A2395

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Castillo M, Kwock L, Green C (1995) MELAS syndrome: imaging and proton MR spectroscopic findings. AJNR Am J Neuroradiol 16(2):233–239

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Clark JM, Marks MP, Adalsteinsson E et al (1996) MELAS: clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy. Neurology 46(1):223–227. https://doi.org/10.1212/wnl.46.1.223

    Article  PubMed  CAS  Google Scholar 

  37. Kaufmann P, Shungu DC, Sano MC, Jhung S, Engelstad K, Mitsis E, Mao X, Shanske S, Hirano M, DiMauro S, De Vivo DC (2004) Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology 62(8):1297–1302. https://doi.org/10.1212/01.wnl.0000120557.83907.a8

    Article  PubMed  CAS  Google Scholar 

  38. Magistretti PJ, Allaman I (2018) Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 19(4):235–249. https://doi.org/10.1038/nrn.2018.19

    Article  PubMed  CAS  Google Scholar 

  39. Vohra R, Kolko M (2020) Lactate: more than merely a metabolic waste product in the inner retina. Mol Neurobiol 57:2021–2037. https://doi.org/10.1007/s12035-019-01863-8

    Article  PubMed  CAS  Google Scholar 

  40. Benarroch EE (2016) Astrocyte signaling and synaptic homeostasis: II: astrocyte-neuron interactions and clinical correlations. Neurology 87(7):726–735. https://doi.org/10.1212/WNL.0000000000003019

    Article  PubMed  Google Scholar 

  41. Chen C, Xiong N, Wang Y et al (2012) A study of familial MELAS: evaluation of A3243G mutation, clinical phenotype, and magnetic resonance spectroscopy-monitored progression. Neurol India 60(1):86–89. https://doi.org/10.4103/0028-3886.93609

    Article  PubMed  Google Scholar 

  42. Boulanger Y, Labelle M, Khiat A (2000) Role of phospholipase A(2) on the variations of the choline signal intensity observed by 1H magnetic resonance spectroscopy in brain diseases. Brain Res Brain Res Rev 33(2–3):380–389. https://doi.org/10.1016/s0165-0173(00)00037-0

    Article  PubMed  CAS  Google Scholar 

  43. Iizuka T, Sakai F (2005) Pathogenesis of stroke-like episodes in MELAS: analysis of neurovascular cellular mechanisms. Curr Neurovasc Res 2(1):29–45. https://doi.org/10.2174/1567202052773544

    Article  PubMed  CAS  Google Scholar 

  44. Tetsuka S, Ogawa T, Hashimoto R, Kato H (2021) Clinical features, pathogenesis, and management of stroke-like episodes due to MELAS. Metab Brain Dis 36(8):2181–2193. https://doi.org/10.1007/s11011-021-00772-x

    Article  PubMed  Google Scholar 

  45. Ross BD (1991) Biochemical considerations in 1H spectroscopy. Glutamate and glutamine; myo-inositol and related metabolites. NMR Biomed. 4(2):59–63. https://doi.org/10.1002/nbm.1940040205

    Article  PubMed  CAS  Google Scholar 

  46. Mandal PK, Guha Roy R, Samkaria A, Maroon JC, Arora Y (2022) In vivo 13C magnetic resonance spectroscopy for assessing brain biochemistry in health and disease. Neurochem Res 47(5):1183–1201. https://doi.org/10.1007/s11064-022-03538-8

    Article  PubMed  CAS  Google Scholar 

  47. Pavlakis SG, Kingsley PB, Kaplan GP, Stacpoole PW, O’Shea M, Lustbader D (1998) Magnetic resonance spectroscopy: use in monitoring MELAS treatment. Arch Neurol 55(6):849–852. https://doi.org/10.1001/archneur.55.6.849

    Article  PubMed  CAS  Google Scholar 

  48. Niu FN, Meng HL, Chang LL et al (2017) Mitochondrial dysfunction and cerebral metabolic abnormalities in patients with mitochondrial encephalomyopathy subtypes: evidence from proton MR spectroscopy and muscle biopsy. CNS Neurosci Ther 23(8):686–697. https://doi.org/10.1111/cns.12714

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Lee HN, Yoon CS, Lee YM (2018) Correlation of serum biomarkers and magnetic resonance spectroscopy in monitoring disease progression in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes due to mtDNA A3243G Mutation. Front Neurol. 9:621. https://doi.org/10.3389/fneur.2018.00621. (Published 2018 Jul 27)

    Article  PubMed  PubMed Central  Google Scholar 

  50. Li Y, Lafontaine M, Chang S, Nelson SJ (2018) Comparison between short and long echo time magnetic resonance spectroscopic imaging at 3T and 7T for evaluating brain metabolites in patients with glioma. ACS Chem Neurosci 9(1):130–137. https://doi.org/10.1021/acschemneuro.7b00286

    Article  PubMed  CAS  Google Scholar 

  51. Lange T, Dydak U, Roberts TP, Rowley HA, Bjeljac M, Boesiger P (2006) Pitfalls in lactate measurements at 3T. AJNR Am J Neuroradiol 27(4):895–901

    PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This research was supported by a grant from the Spanish Fundación Eugenio Rodríguez Pascual and the Fundación Mutua Madrileña. The financial sponsors had no role in the analysis or the development of conclusions. The investigators are solely responsible for the content and the decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Neurology Department, Neuromuscular Disorders Unit, University Hospital, 12 de Octubre Avda. de Córdoba, S/N 28041, Madrid, Spain

    María Paz Guerrero-Molina & Cristina Domínguez-González

  2. Magnetic Resonance Department, Inscanner SL, Alicant, Spain

    Ángela Bernabeu-Sanz

  3. Department of Neuroradiology, University Hospital, 12 de Octubre, Madrid, Spain

    Ana Ramos-González

  4. Department of Internal Medicine, University Hospital, 12 de Octubre, Madrid, Spain

    Montserrat Morales-Conejo

  5. National Reference Center for Congenital Errors of Metabolism (CSUR) an European Reference Center for Inherited Metabolic Disease (MetabERN), University Hospital, 12 de Octubre, Madrid, Spain

    Montserrat Morales-Conejo, Cristina Domínguez-González & Jesús González de la Aleja

  6. Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, Madrid, Spain

    Montserrat Morales-Conejo, Aitor Delmiro, Cristina Domínguez-González, Joaquín Arenas & Miguel A. Martín

  7. Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigación Sanitaria Hospital, 12 de Octubre’ (‘imas12’), Madrid, Spain

    Aitor Delmiro, Joaquín Arenas & Miguel A. Martín

  8. Research Institute (‘imas12’), University Hospital, 12 de Octubre, Madrid, Spain

    Aitor Delmiro, Cristina Domínguez-González, Joaquín Arenas & Miguel A. Martín

  9. Neurology Department, Epilepsy Unit, University Hospital, 12 de Octubre, Madrid, Spain

    Jesús González de la Aleja

Authors
  1. María Paz Guerrero-Molina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ángela Bernabeu-Sanz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Ramos-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Montserrat Morales-Conejo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aitor Delmiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cristina Domínguez-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joaquín Arenas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Miguel A. Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jesús González de la Aleja
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to María Paz Guerrero-Molina.

Ethics declarations

Ethical approval

This study received approval from the Ethics Committee of the University Hospital 12 de Octubre (Madrid, Spain; approval number: 20/032).

Informed consent

All subjects provided written informed consent.

Conflict of interest

We have no Conflict of Interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guerrero-Molina, M.P., Bernabeu-Sanz, Á., Ramos-González, A. et al. Magnetic resonance spectroscopy in MELAS syndrome: correlation with CSF and plasma metabolite levels and change after glutamine supplementation. Neuroradiology 66, 389–398 (2024). https://doi.org/10.1007/s00234-023-03263-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00234-023-03263-1

Keywords

Search

Navigation