Skip to main content
Log in

MR spectroscopy and imaging-derived measurements in the supplementary motor area for biomarkers of amyotrophic lateral sclerosis

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

The diagnosis of amyotrophic lateral sclerosis (ALS) requires both upper and lower motor neuron signs. However, quite a few patients with ALS lack the upper motor neuron sign during the disease. This study sought to investigate whether metabolites, including glutamate (Glu), N-acetyl aspartate (NAA), and gamma aminobutyric acid (GABA), in the supplementary motor area (SMA) measured by magnetic resonance spectroscopy (MRS), could be a surrogate biomarker for ALS. Twenty-five patients with ALS and 12 controls underwent 3.0-T MR scanning, which measured Glu, NAA, and GABA. Finally, receiver operating characteristic (ROC) curves were created and the area under curve (AUC) was calculated to assess the diagnostic power. Logistic regression analysis revealed the usefulness of both Glu and NAA for the differentiation of ALS from controls (Glu, P = 0.009; NAA, P = 0.033). The ratio of Glu to NAA or GABA was significantly increased in patients with ALS (Glu/NAA, P = 0.027; Glu/GABA, P = 0.003). Both the AUCs were more than 0.7, with high specificity but low sensitivity. The present findings might indicate that both the Glu/NAA and the Glu/GABA ratios in the SMA could be potential biomarkers for the diagnosis of ALS.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Riku Y, Atsuta N, Yoshida M, Tatsumi S, Iwasaki Y, Mimuro M, Watanabe H, Ito M, Senda J, Nakamura R, Koike H, Sobue G (2014) Differential motor neuron involvement in progressive muscular atrophy: a comparative study with amyotrophic lateral sclerosis. BMJ Open 4(5):e005213

    Article  PubMed  PubMed Central  Google Scholar 

  2. Novotny EJ Jr, Fulbright RK, Pearl PL, Gibson KM, Rothman DL (2003) Magnetic resonance spectroscopy of neurotransmitters in human brain. Ann Neurol 54(Suppl 6):S25–S31

    Article  CAS  PubMed  Google Scholar 

  3. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377(9769):942–955

    Article  CAS  PubMed  Google Scholar 

  4. Bradley WG, Bowen BC, Pattany PM, Rotta F (1999) 1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis. J Neurol Sci 169(1-2):84–86

    Article  CAS  PubMed  Google Scholar 

  5. Pioro EP, Majors AW, Mitsumoto H, Nelson DR, Ng TC (1999) 1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla. Neurology 53(1):71–79

    Article  CAS  PubMed  Google Scholar 

  6. Bowen BC, Pattany PM, Bradley WG, Murdoch JB, Rotta F, Younis AA, Duncan RC, Quencer RM (2000) MR imaging and localized proton spectroscopy of the precentral gyrus in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol 21(4):647–658

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Pohl C, Block W, Karitzky J, Traber F, Schmidt S, Grothe C et al (2001) Proton magnetic resonance spectroscopy of the motor cortex in 70 patients with amyotrophic lateral sclerosis. Arch Neurol 58(5):729–735

    Article  CAS  PubMed  Google Scholar 

  8. Schuff N, Rooney WD, Miller R, Gelinas DF, Amend DL, Maudsley AA, Weiner MW (2001) Reanalysis of multislice (1)H MRSI in amyotrophic lateral sclerosis. Magn Reson Med 45(3):513–516

    Article  CAS  PubMed  Google Scholar 

  9. Rule RR, Suhy J, Schuff N, Gelinas DF, Miller RG, Weiner MW (2004) Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study. Amyotroph Lateral Scler Other Motor Neuron Disord 5(3):141–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang S, Poptani H, Woo JH, Desiderio LM, Elman LB, McCluskey LF et al (2006) Amyotrophic lateral sclerosis: diffusion-tensor and chemical shift MR imaging at 3.0 T. Radiology 239(3):831–838

    Article  PubMed  Google Scholar 

  11. Mitsumoto H, Ulug AM, Pullman SL, Gooch CL, Chan S, Tang MX et al (2007) Quantitative objective markers for upper and lower motor neuron dysfunction in ALS. Neurology 68(17):1402–1410

    Article  CAS  PubMed  Google Scholar 

  12. Unrath A, Ludolph AC, Kassubek J (2007) Brain metabolites in definite amyotrophic lateral sclerosis. A longitudinal proton magnetic resonance spectroscopy study. J Neurol 254(8):1099–1106

    Article  CAS  PubMed  Google Scholar 

  13. Sivak S, Bittsansky M, Kurca E, Turcanova-Koprusakova M, Grofik M, Nosal V et al (2010) Proton magnetic resonance spectroscopy in patients with early stages of amyotrophic lateral sclerosis. Neuroradiology 52(12):1079–1085

    Article  PubMed  Google Scholar 

  14. Verma G, Woo JH, Chawla S, Wang S, Sheriff S, Elman LB, McCluskey LF, Grossman M, Melhem ER, Maudsley AA, Poptani H (2013) Whole-brain analysis of amyotrophic lateral sclerosis by using echo-planar spectroscopic imaging. Radiology 267(3):851–857

    Article  PubMed  PubMed Central  Google Scholar 

  15. Han J, Ma L (2010) Study of the features of proton MR spectroscopy ((1)H-MRS) on amyotrophic lateral sclerosis. J Magn Reson Imaging 31(2):305–308

    Article  PubMed  Google Scholar 

  16. Foerster BR, Callaghan BC, Petrou M, Edden RA, Chenevert TL, Feldman EL (2012) Decreased motor cortex gamma-aminobutyric acid in amyotrophic lateral sclerosis. Neurology 78(20):1596–1600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Foerster BR, Pomper MG, Callaghan BC, Petrou M, Edden RA, Mohamed MA et al (2013) An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy. JAMA Neurol 70(8):1009–1016

    Article  PubMed  PubMed Central  Google Scholar 

  18. Foerster BR, Carlos RC, Dwamena BA, Callaghan BC, Petrou M, Edden RA et al (2014) Multimodal MRI as a diagnostic biomarker for amyotrophic lateral sclerosis. Ann Clin Transl Neurol 1(2):107–114

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sako W, Abe T, Izumi Y, Harada M, Kaji R (2016) The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis. J Clin Neurosci 27:110–113

    Article  CAS  PubMed  Google Scholar 

  20. Atassi N, Xu M, Triantafyllou C, Keil B, Lawson R, Cernasov P, Ratti E, Long CJ, Paganoni S, Murphy A, Salibi N, Seethamraju R, Rosen B, Ratai EM (2017) Ultra high-field (7tesla) magnetic resonance spectroscopy in amyotrophic lateral sclerosis. PLoS One 12(5):e0177680

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Cheong I, Marjanska M, Deelchand DK, Eberly LE, Walk D, Oz G (2017) Ultra-high field proton MR spectroscopy in early-stage amyotrophic lateral sclerosis. Neurochem Res 42(6):1833–1844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC (2011) Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. J Neurol Neurosurg Psychiatry 82(5):476–486

    Article  PubMed  Google Scholar 

  23. Sako W, Abe T, Izumi Y, Harada M, Kaji R (2016) Fractional anisotropy in the supplementary motor area correlates with disease duration and severity of amyotrophic lateral sclerosis. Neurol Sci 37(4):573–577

    Article  PubMed  Google Scholar 

  24. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15(1):273–289

    Article  CAS  PubMed  Google Scholar 

  25. Sako W, Fujita K, Vo A, Rucker JC, Rizzo JR, Niethammer M, Carbon M, Bressman SB, Uluğ AM, Eidelberg D (2015) The visual perception of natural motion: abnormal task-related neural activity in DYT1 dystonia. Brain 138(Pt 12):3598–3609

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sako W, Abe T, Izumi Y, Yamazaki H, Matsui N, Harada M, Kaji R (2017) Spontaneous brain activity in the sensorimotor cortex in amyotrophic lateral sclerosis can be negatively regulated by corticospinal fiber integrity. Neurol Sci 38(5):755–760

    Article  PubMed  Google Scholar 

  27. Jenkinson M, Bannister P, Brady M, Smith S (2002) Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17(2):825–841

    Article  PubMed  Google Scholar 

  28. Biswal B, Yetkin FZ, Haughton VM, Hyde JS (1995) Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 34(4):537–541

    Article  CAS  PubMed  Google Scholar 

  29. Lowe MJ, Mock BJ, Sorenson JA (1998) Functional connectivity in single and multislice echoplanar imaging using resting-state fluctuations. Neuroimage 7(2):119–132

    Article  CAS  PubMed  Google Scholar 

  30. Zang Y, Jiang T, Lu Y, He Y, Tian L (2004) Regional homogeneity approach to fMRI data analysis. Neuroimage 22(1):394–400

    Article  PubMed  Google Scholar 

  31. Block W, Karitzky J, Traber F, Pohl C, Keller E, Mundegar RR et al (1998) Proton magnetic resonance spectroscopy of the primary motor cortex in patients with motor neuron disease: subgroup analysis and follow-up measurements. Arch Neurol 55(7):931–936

    Article  CAS  PubMed  Google Scholar 

  32. Cheong I, Deelchand DK, Eberly LE, Marjańska M, Manousakis G, Guliani G, Walk D, Öz G (2019) Neurochemical correlates of functional decline in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 90(3):294–301

    Article  PubMed  Google Scholar 

  33. Fiszman ML, Ricart KC, Latini A, Rodriguez G, Sica RE (2010) In vitro neurotoxic properties and excitatory aminoacids concentration in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Relationship with the degree of certainty of disease diagnoses. Acta Neurol Scand 121(2):120–126

    Article  CAS  PubMed  Google Scholar 

  34. Milanese M, Giribaldi F, Melone M, Bonifacino T, Musante I, Carminati E, Rossi PIA, Vergani L, Voci A, Conti F, Puliti A, Bonanno G (2014) Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 64:48–59

    Article  CAS  PubMed  Google Scholar 

  35. Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326(22):1464–1468

    Article  CAS  PubMed  Google Scholar 

  36. Sage CA, Peeters RR, Gorner A, Robberecht W, Sunaert S (2007) Quantitative diffusion tensor imaging in amyotrophic lateral sclerosis. Neuroimage 34(2):486–499

    Article  PubMed  Google Scholar 

  37. Mohammadi B, Kollewe K, Samii A, Krampfl K, Dengler R, Munte TF (2009) Changes of resting state brain networks in amyotrophic lateral sclerosis. Exp Neurol 217(1):147–153

    Article  PubMed  Google Scholar 

  38. Keil C, Prell T, Peschel T, Hartung V, Dengler R, Grosskreutz J (2012) Longitudinal diffusion tensor imaging in amyotrophic lateral sclerosis. BMC Neurosci 13:141

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhang J, Yin X, Zhao L, Evans AC, Song L, Xie B, Li H, Luo C, Wang J (2014) Regional alterations in cortical thickness and white matter integrity in amyotrophic lateral sclerosis. J Neurol 261(2):412–421

    Article  PubMed  Google Scholar 

  40. Corcia P, Tauber C, Vercoullie J, Arlicot N, Prunier C, Praline J, Nicolas G, Venel Y, Hommet C, Baulieu JL, Cottier JP, Roussel C, Kassiou M, Guilloteau D, Ribeiro MJ (2012) Molecular imaging of microglial activation in amyotrophic lateral sclerosis. PLoS One 7(12):e52941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all the subjects for joining this study.

Funding

This study was supported by the Uehara Memorial Foundation, Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 20K12670, and Grants-in Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wataru Sako.

Ethics declarations

Ethical approval and informed consent statement

All subjects provided written informed consent, following detailed explanation of the procedures, and the study was approved by the local ethics committee of Tokushima University Hospital. This study was performed according to the Declaration of Helsinki.

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s note

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

Supplementary Information

Supplementary Figure 1.

Differences in FA and ReHo, and results of correlation analyses. There were no significant differences in FA and ReHo between groups (A). ALS, amyotrophic lateral sclerosis; Ctr, control; FA value was positively correlated with ReHo. FA, fractional anisotropy; ReHo, regional homogeneity. (PNG 90 kb)

High resolution image (TIF 123 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sako, W., Izumi, Y., Abe, T. et al. MR spectroscopy and imaging-derived measurements in the supplementary motor area for biomarkers of amyotrophic lateral sclerosis. Neurol Sci 42, 4257–4263 (2021). https://doi.org/10.1007/s10072-021-05107-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-021-05107-3

Keywords

Navigation