Metabolic abnormality in acute stroke-like lesion and its relationship with focal cerebral blood flow in patients with MELAS: Evidence from proton MR spectroscopy and arterial spin labeling
Introduction
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common type of mitochondrial disease (El-Hattab et al., 2015b). It is a rare maternally inherited genetic disease mostly affecting children and young adults (Pavlakis et al., 1984). The symptoms of MELAS include stroke-like episodes (SLEs), growth retardation, dementia, easy fatigability, endocrinopathies, gastrointestinal dysmotility and diabetes mellitus, etc. (Koenig et al., 2016). Among these symptoms, SLE is not only a cardinal feature occurring in 84–99% of affected individuals, but also a crucial factor determining the prognosis of MELAS (Yatsuga et al., 2012). These episodes present with protean clinical manifestations including headaches, seizures, hearing loss, cortical blindness, aphasia and motor weakness (El-Hattab et al., 2015a). Although the molecular basis of MELAS that adenine to guanine transition at position 3243 of mtDNA (m.3243A > G) in the MT-TL1 gene encoding tRNALeu(UUR) has been elucidated (Goto et al., 1990, Kobayashi et al., 1990); the pathogenesis of SLEs remain controversial. Possible hypotheses include mitochondrial angiopathy leading to ischemic change, mitochondrial cytopathy caused by an oxidative phosphorylation defect, or non-ischemic neurovascular events initiated by neuronal hyperexcitability (Iizuka and Sakai, 2005).
Cerebral stroke-like lesions (SLLs) are morphological equivalent of SLEs showing on magnetic resonance imaging (MRI) (Malhotra and Liebeskind, 2016). Typical MRI findings in an acute SLL include gyral swelling, subcortical white matter hyperintensity on T2 fluid-attenuated inversion recovery (FLAIR) and cortical diffusion restriction (Ito et al., 2011). Conventional MRI imaging techniques provide pivotal information of morphological abnormalities for diagnosing MELAS, while several other imaging approaches have emerged that provide new dimensions in the evaluation of such SLLs. Proton magnetic resonance spectroscopy (1H-MRS) and arterial spin labeling (ASL) are non-invasive MRI-based techniques that can reflect metabolic and perfusion information of brain tissue, respectively (Gai et al., 2011, Laxer, 1997). Previous studies have reported increased cerebral blood flow (CBF) and lactate (Lac) level, as well as decreased N-acetyl aspartate (NAA) level in acute SLLs at acute stage of SLEs in MELAS using the combination of ASL and 1H-MRS (Li et al., 2017b, Tsujikawa et al., 2010). These findings demonstrated that focal hyperperfusion and anaerobic metabolism occurred in acute SLLs. However, these two studies are case reports rather than prospective cohorts, and the relationships between CBF and metabolites in acute SLLs remain unclear, which need to be further studied.
In this study, we aimed to evaluate the changes of MRS-derived metabolite levels in acute SLLs of MELAS patients, and further assess the quantitative correlations between these metabolite concentrations and focal CBF. We hypothesized that there may be inherent correlations between focal hyperperfusion and metabolic abnormalities in the brain lesions, which could contribute to better understanding of the pathogenesis for MELAS.
Section snippets
Subjects
The study was approved by the Institutional Review Board of our hospital and was conducted in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.
All patients were examined by a specialized neurologist with over 15 years’ experience in MELAS. The diagnosis of MELAS was based on clinical manifestation, MRI, muscle biopsy and genetic testing. Specifically, 23 patients with MELAS at acute stage (within 1 week after SLEs) were
Demographic and clinical features
The demographical and clinical features of the patients were shown in Table 1 and Table S1. A total of 23 MELAS patients (male = 12, female = 11; age, mean = 24.1 years, range = 14–60 years) at acute stage and 20 healthy subjects (male = 11, female = 9; age, mean = 25.8 years, range = 18–56 years) were recruited in this study. The MELAS group and NC group did not differ significantly regarding age (p = 0.553) or gender (p = 0.826). In MELAS group, there were 19 individuals carrying m.3243A > G
Discussion
This is the first study to determine the inherent relationship between metabolite concentration and cerebral perfusion of acute SLLs in MELAS patients with the comprehensive use of 1H-MRS and ASL. Two main findings were demonstrated in present study: first, MELAS patients exhibited significant metabolite abnormalities in acute SLLs; second, lactate level in acute SLLs was positively correlated with focal rCBF in MELAS patients.
Single-voxel 1H-MRS technique is widely used to assess brain
Conclusions
In summary, our results demonstrated that metabolic alterations occurred in acute SLLs of MELAS patients at acute stage, which could clarify the biochemical mechanism of brain damage in these lesions. Furthermore, we also exhibited the intrinsic associations between Lac level and rCBF in acute SLLs, suggesting lactate accumulation may contribute to focal hyperperfusion. Thereby, our findings confirmed that both mitochondrial cytopathy and mitochondrial angiopathy play crucial roles in the
Funding
This study was supported by the Science and Technology Commission of Shanghai Municipality (19411951200, 19ZR1407900).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors sincerely thank all patients with MELAS and their families who kindly agreed to participate in the present study.
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Co-First author: Rong Wang, MD and Bin Hu contribute equally to this study.