MR evaluation of cerebral oxygen metabolism and blood flow in stroke-like episodes of MELAS

Abstract

Metabolic information is essential in the investigation of the pathophysiology of stroke-like episodes in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Here, we used magnetic resonance imaging to evaluate the dynamic metabolic changes before and after a stroke-like episode in two patients with MELAS caused by the mitochondrial DNA mutation A3243G. We performed functional magnetic resonance imaging, including arterial spin labeling and oxygen extraction fraction imaging, and generated cerebral blood flow and oxygen extraction fraction maps. We recruited eight healthy volunteers to define the normal range of the oxygen extraction fraction. We detected a heterogeneous reduction in the oxygen extraction fraction in the brain in the interictal period as well as at the onset of a stroke-like attack. However, the oxygen extraction fraction in the stroke-like lesions normalized in the acute stage. The stroke-like lesions showed consistent hyperperfusion in the acute phase but hypoperfusion in the chronic phase. We have demonstrated the utility of using new magnetic resonance imaging techniques in the evaluation of the pathophysiology of stroke-like lesions. The increased utilization of oxygen in an acute lesion is a novel finding in our study, which might play a role in the oxidative stress.

Introduction

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited encephalomyopathy, characterized by seizures, headaches, lactic acidosis, vomiting, and recurrent stroke-like episodes [1]. It is mainly associated with mitochondrial DNA mutations, mostly A3243G, which cause a failure of mitochondrial protein synthesis resulting in impaired ATP production. In contrast to the rapid progress in understanding the molecular pathophysiology of MELAS, the precise pathogenesis of the stroke-like episodes remains controversial. Possible mechanisms include angiopathy leading to ischemic change [2], energy failure caused by defects in the oxidative metabolic pathways of energy production [3], [4], or increased energy demand because of neuronal hyperexcitability [4].

To clarify the mechanisms of the stroke-like episodes in MELAS, investigators have assessed various pathophysiological parameters of the cerebral lesions in vivo by neuroimaging. There have been many studies concerning changes in cerebral blood flow in patients with MELAS, which have revealed hyperperfusion in the acute stage (within 1 month) and hypoperfusion in the chronic stage (several months later) [[4], [5], [6], [7], [8], [9], [10]]. There have been a few studies of the metabolic condition in the stroke-like episodes, including oxygen uptake, glucose metabolism, and oxidative stress [10], [11], [12]. Using single-photon emission computed tomography or PET, increased glucose metabolism [10], [11], decreased cerebral oxygen metabolism [11], [12], and mild increased oxidative stress have been observed in the acute stage of stroke-like lesions [10]. A drastic decrease in cerebral oxygen metabolism and cerebral glucose uptake was found globally in the brains of interictal MELAS patients [13], [14], [15].

Most of these studies were cross-sectional, but serial studies could provide more valuable information for the longitudinal evaluation of the pathophysiology of stroke-like lesions. However, PET is not ideal for serial studies because of its high cost and necessary radiation exposure. With the recent development of new MRI techniques, patients can be followed-up frequently and noninvasively. Recently, Tsujikawa et al. used continuous arterial spin labeling (ASL) to assess cerebral blood flow in MELAS patients [16]. Oxygen extraction fraction (OEF) imaging is a newly developed technique that enables quantitative assessment of the OEF in brain tissue using MRI. This technique has been tested in volunteers and was able to show a decrease in OEF caused by hypercapnia [17]. It has also been used to detect misery perfusion, which is characterized by elevated oxygenation in the ischemic region [18]. It is possible that OEF imaging could be used to assess oxygenation in the stroke-like episodes of MELAS patients.

The purpose of our study was to assess the dynamic metabolic changes during the development of stroke-like lesions in patients with MELAS. Metabolic information was obtained by functional MRI, including measurements of the ADC, CBF, and OEF.