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

Abstract

Purpose: To establish a brain proton magnetic resonance spectroscopy (¹H 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 ¹H 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 ¹H MRS and T₂-weighted imaging (T₂WI) were longitudinally performed in the same individuals at 5, 7, and 9 weeks of age.

Results: Brain ¹H 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 T₂WI. 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 ¹H 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 T₂WI.

Conclusion: Using brain ¹H 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.

Keywords: Lactate; Leigh syndrome; Magnetic resonance spectroscopy; Mitochondrial disease.