Detection of increased intracerebral lactate in a mouse model of Leigh syndrome using proton MR spectroscopy

Yusuke Takahashi, Hidetaka Kioka, Yasunori Shintani, Akiko Ohki, Seiji Takashima, Yasushi Sakata, Takahiro Higuchi, Shigeyoshi Saito

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Purpose: To establish a brain proton magnetic resonance spectroscopy ( 1 H MRS) experimental system using a mouse model of Leigh syndrome for monitoring intracerebral lactate levels as a biomarker of mitochondrial disease progression. Materials and methods: Brain 1 H MRS was performed in the Ndufs4 homozygous knockout (KO) mice, a mouse model of Leigh syndrome, and control mice on a horizontal 7.0-T magnetic resonance imaging system at age 5–9 weeks. In a subset of KO mice, survival analysis was performed according to the median of the intracerebral lactate levels. In addition, in KO mice alive until 9 weeks of age, both 1 H MRS and T 2 -weighted imaging (T 2 WI) were longitudinally performed in the same individuals at 5, 7, and 9 weeks of age. Results: Brain 1 H MRS demonstrated increased lactate levels in KO mice compared with control mice (6.4 ± 1.2 mM vs. 3.3 ± 0.8 mM, p < 0.0001). The increased intracerebral lactate levels were already observed at 5 weeks of age, while no obvious abnormal findings were detected in T 2 WI. Notably, an increased lactate level of >5.94 mM at week 5 was associated with a poor prognosis (median survival days: 24.5 vs. 42 days, log-rank p = 0.03). Longitudinal 1 H MRS experiments revealed temporal increase of intracerebral lactate levels, peaking at week 7 (mean change: 2.6 ± 0.7 mM, p = 0.001), followed by decrease at week 9 (mean change: −3.8 ± 2.5 mM, p = 0.03), along with further disease progression, with brain lesions being detected on T 2 WI. Conclusion: Using brain 1 H MRS, we demonstrated significant increase in intracerebral lactate levels in a mouse model of Leigh syndrome. Additionally, we demonstrated that intracerebral lactate is a useful biomarker of mitochondrial disease progression at stages preceding the development of brain lesions.

Original languageEnglish
Pages (from-to)38-43
Number of pages6
JournalMagnetic Resonance Imaging
Volume58
DOIs
Publication statusPublished - May 2019
Externally publishedYes

Keywords

  • Lactate
  • Leigh syndrome
  • Magnetic resonance spectroscopy
  • Mitochondrial disease

ASJC Scopus subject areas

  • Biophysics
  • Biomedical Engineering
  • Radiology Nuclear Medicine and imaging

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