Early detection of elevated lactate levels in a mitochondrial disease model using chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) with 7T MR imaging

  • Shigeyoshi SaitoEmail author
  • Yusuke Takahashi
  • Akiko Ohki
  • Yasunori Shintani
  • Takahiro Higuchi
Author’s reply to Letter to the Editor

To the Editor,

We appreciate the letter in response to our article [1]. Our report revealed that chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) using 7T magnetic resonance imaging (MRI) could detect lactate level elevation prior to the formation of cerebral morphological abnormalities in Ndufs4 knockout (KO) mice, a mouse model of Leigh syndrome [1].

The letter claimed that Ndufs4 KO mice investigated in the present study do not represent an animal model of Leigh syndrome. We performed MRI and CEST in the mice when they were 6 weeks of age. They did not show any lesions in T2-weighted MRI (T2WI), but at around 8 weeks of age they manifested Leigh syndrome features with 100% penetrance. Ndufs4 KO mice that we used in this study were produced and well established as a model of Leigh syndrome by the Palmiter Laboratory at the University of Washington [2, 3]. A model of Leigh syndrome is characterized by failure to thrive, generalized hypotonia,...


Ndufs4 knockout Leigh syndrome Chemical exchange saturation transfer Magnetic resonance spectroscopy 



This work was supported by Grants-in-Aid for Scientific Research (Kakenhi, Nos. 16K090170 and 15K21774) from the Japan Society for the Promotion of Science (JSPS).

Compliance with ethical standards

Conflicts of interest

The authors have no conflicts of interest to report.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.


  1. 1.
    Saito S, Takahashi Y, Ohki A, Shintani Y, Higuchi T. Early detection of elevated lactate levels in a mitochondrial disease model using chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) at 7T-MRI. Radiol Phys Technol. 2019;12(1):46–54.CrossRefGoogle Scholar
  2. 2.
    Kruse SE, Watt WC, Marcinek DJ, Kapur RP, Schenkman KA, Palmiter RD. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 2008;7(4):312–20.CrossRefGoogle Scholar
  3. 3.
    Quintana A, Kruse SE, Kapur RP, Sanz E, Palmiter RD. Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome. Proc Natl Acad Sci USA. 2010;107(24):10996–1001.CrossRefGoogle Scholar
  4. 4.
    Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol. 2008;39(4):223–35.CrossRefGoogle Scholar
  5. 5.
    Takahashi Y, Kioka H, Shintani Y, Ohki A, Takashima S, Sakata Y, Higuchi T, Saito S. Detection of increased intracerebral lactate in a mouse model of Leigh syndrome using proton MR spectroscopy. Magn Reson Imaging. 2019;58:38–43.CrossRefGoogle Scholar
  6. 6.
    Kaufmann P, Shungu DC, Sano MC, Jhung S, Engelstad K, Mitsis E, Mao X, Shanske S, Hirano M, DiMauro S, De Vivo DC. Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology. 2004;62(8):1297–302.CrossRefGoogle Scholar
  7. 7.
    Boddaert N, Romano S, Funalot B, Rio M, Sarzi E, Lebre AS, Bahi-Buisson N, Valayannopoulos V, Desguerre I, Seidenwurm D, Brunelle F, Brami-Zylberberg F, Rotig A, Munnich A, de Lonlay P. 1H MRS spectroscopy evidence of cerebellar high lactate in mitochondrial respiratory chain deficiency. Mol Genet Metab. 2008;93(1):85–8.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Radiological Technology and Japan Society of Medical Physics 2019

Authors and Affiliations

  1. 1.Division of Health Sciences, Department of Medical Physics and EngineeringOsaka University Graduate School of MedicineSuitaJapan
  2. 2.Department of Biomedical ImagingNational Cardiovascular and Cerebral Research CenterSuitaJapan
  3. 3.Department of Cardiovascular MedicineOsaka University Graduate School of MedicineSuitaJapan
  4. 4.Department of Medical BiochemistryOsaka University Graduate School of Frontier BioscienceSuitaJapan
  5. 5.Comprehensive Heart Failure CenterUniversity of WuerzburgWürzburgGermany
  6. 6.Department of Nuclear MedicineUniversity of WuerzburgWürzburgGermany

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