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

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

Fingerprint

Leigh Disease
Protons
Lactic Acid
Brain
Magnetic Resonance Spectroscopy
Spectroscopy
Knockout Mice
Disease Progression
Mitochondrial Diseases
Biomarkers
Magnetic resonance spectroscopy
Imaging techniques
Magnetic resonance
Survival Analysis
Imaging systems
Magnetic Resonance Imaging
Nuclear magnetic resonance
Monitoring

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biomedical Engineering
  • Radiology Nuclear Medicine and imaging

Cite this

Detection of increased intracerebral lactate in a mouse model of Leigh syndrome using proton MR spectroscopy. / Takahashi, Yusuke; Kioka, Hidetaka; Shintani, Yasunori; Ohki, Akiko; Takashima, Seiji; Sakata, Yasushi; Higuchi, Takahiro; Saito, Shigeyoshi.

In: Magnetic Resonance Imaging, Vol. 58, 05.2019, p. 38-43.

Research output: Contribution to journalArticle

Takahashi, Yusuke ; Kioka, Hidetaka ; Shintani, Yasunori ; Ohki, Akiko ; Takashima, Seiji ; Sakata, Yasushi ; Higuchi, Takahiro ; Saito, Shigeyoshi. / Detection of increased intracerebral lactate in a mouse model of Leigh syndrome using proton MR spectroscopy. In: Magnetic Resonance Imaging. 2019 ; Vol. 58. pp. 38-43.
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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.",
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AU - Takahashi, Yusuke

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AU - Ohki, Akiko

AU - Takashima, Seiji

AU - Sakata, Yasushi

AU - Higuchi, Takahiro

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