Yusuke Takahashi1, Hidetaka Kioka1, Yasunori Shintani2, Akiko Ohki3, Seiji Takashima2, Yasushi Sakata1, Takahiro Higuchi4, Shigeyoshi Saito5. 1. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. 2. Department of Medical Biochemistry, Osaka University Graduate School of Frontier Bioscience, Suita, Osaka 565-0871, Japan. 3. Department of Biomedical Imaging, National Cardiovascular and Cerebral Research Center, Suita, Osaka 565-8565, Japan. 4. Department of Biomedical Imaging, National Cardiovascular and Cerebral Research Center, Suita, Osaka 565-8565, Japan; Comprehensive Heart Failure Center, University of Wuerzburg, Wuerzburg 97078, Germany; Department of Nuclear Medicine, University of Wuerzburg, Wuerzburg 97078, Germany. 5. Department of Biomedical Imaging, National Cardiovascular and Cerebral Research Center, Suita, Osaka 565-8565, Japan; Department of Medical Physics and Engineering, Division of Health Sciences, Osaka University Graduate School of Medicine, Suita, Osaka 560-0871, Japan. Electronic address: saito@sahs.med.osaka-u.ac.jp.
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.
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.
Authors: Melissa A E van de Wal; Merel J W Adjobo-Hermans; Jaap Keijer; Tom J J Schirris; Judith R Homberg; Mariusz R Wieckowski; Sander Grefte; Evert M van Schothorst; Clara van Karnebeek; Albert Quintana; Werner J H Koopman Journal: Brain Date: 2022-03-29 Impact factor: 13.501
Authors: Simon C Johnson; Ernst-Bernhard Kayser; Rebecca Bornstein; Julia Stokes; Alessandro Bitto; Kyung Yeon Park; Amanda Pan; Grace Sun; Daniel Raftery; Matt Kaeberlein; Margaret M Sedensky; Philip G Morgan Journal: Mol Genet Metab Date: 2020-04-03 Impact factor: 4.204
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