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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

  • Shigeyoshi SaitoEmail author
  • Yusuke Takahashi
  • Akiko Ohki
  • Yasunori Shintani
  • Takahiro Higuchi
Article

Abstract

This study aimed to use chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) at 7T-MRI for early detection of intracerebral lactate in a mitochondrial disease model without brain lesions. We considered Ndufs4-knockout (KO) mice as Leigh syndrome models and wild-type (WT) mice as control mice. Brain MRI and 1H-MRS were performed. T2WI data acquired with the Rapid Acquisition with Refocused Echoes (RARE) sequence were used for evaluation of brain lesions. CEST imaging of mice brains was performed using RARE with a magnetization transfer (MT) pulse. The MT ratio (MTR) asymmetry curves and five MTR asymmetry maps at 0.5, 1.0, 2.0, 3.0, and 3.5 ppm were calculated using these CEST images. Metabolite concentrations were measured by MRS. T2WI MRI revealed no obvious abnormal findings in KO and WT mice brains at 6 weeks of age. The MTR asymmetry maps at 0.5 ppm, 1.0 ppm, and 2.0 ppm of the KO mice were higher than those of the control mice. Brain 1H MRS revealed a significant increase in lactate levels in all KO mice in comparison with those in the control mice. Additionally, creatine levels in the KO mice were slightly higher than those in the control mice. The levels of the other four metabolites—mIns, NAA + NAAG, GPC + PCh, and Glu + Gln—did not change significantly. We propose that CEST imaging can be used as a biomarker of intracerebral elevated lactate levels in mitochondrial disease.

Keywords

Mitochondrial disease Chemical exchange saturation transfer Magnetic resonance spectroscopy Magnetic resonance imaging 

Abbreviations

ATP

Adenosine triphosphate

CEST

Chemical exchange saturation transfer

CSI

Chemical shift imaging

FASTMAP

Fast automated shimming technique by mapping along projections

KO

Knock out

mM

Mmol/L

MTR

Magnetization transfer ratio

MR

Magnetic resonance

MRI

Magnetic resonance imaging

NOE

Nuclear overhauser enhancements

PRESS

Point resolved spectroscopy

RARE

Rapid acquisition with refocused echoes

SD

Standard deviation

TE

Echo time

TR

Repetition time

T2WI

T2-weighted images

VAPOR

Variable power RF pulses with optimized relaxation delays

WT

Wild type

WASSR

Water saturation shift referencing

1H MRS

Proton magnetic resonance spectroscopy

Notes

Acknowledgements

We thank Dr. Rikita Araki (Bruker Biospin) for CEST calculation used in the current study.

Funding

This work was supported by Grants-in-Aid for Scientific Research (Kakenhi, No. 16K090170 and 15K21774) from the Japan Society for the Promotion of Science (JSPS).

Compliance with ethical standards

Conflict of interest

The authors declare no financial or commercial conflicts of interest.

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.

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Copyright information

© Japanese Society of Radiological Technology and Japan Society of Medical Physics 2018

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 WuerzburgWuerzburgGermany
  6. 6.Department of Nuclear MedicineUniversity of WuerzburgWuerzburgGermany

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