Magnetic resonance spectroscopy in patients with MELAS

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Abstract

Localized magnetic resonance spectroscopy (MRS) yields sensitive metabolic markers to provide insight into the pathophysiology of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) in vivo. Findings in full MELAS syndrome at 1H MRS of the brain typically include severely elevated lactate and reduced N-acetylaspartate, glutamate, myo-inositol, and total creatine concentrations in stroke-like lesions. Similar but less extreme alterations are also common in gray matter (GM) regions that appear normal at magnetic resonance imaging. Phosphorus spectroscopy of peripheral muscle permits investigation of the bioenergetic status. A decline of the phosphorylation potential indicates a low energy reserve at rest. Phosphocreatine resynthesis during post-exercise recovery is delayed pointing to reduced mitochondrial capacity. As MRS is inherently non-invasive, follow-up studies can be performed to assess treatment response quantitatively.

Introduction

Common biochemical defects of the maternally inherited syndrome of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) are impaired complex I or IV activities or multiple defects of respiratory chain enzymes [1]. The clinical phenotype of classical MELAS syndrome is characterized by stroke-like episodes, epilepsy, vision loss, progressive dementia, accumulation of lactate (Lac), migrainous headaches, vomiting, and exercise intolerance. The observed infarcts, which show up as hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) scans, are assumed to be non-vascular and due to transient oxidative-phosphorylation (OxPhos) dysfunction within the brain parenchyma. A mitochondrial DNA (mtDNA) point mutation at nucleotide position 3243 or (less frequently) 3271 is most often the underlying genetic factor of the disease.

Localized magnetic resonance spectroscopy (MRS) has been applied for two decades to the investigation of patients with MELAS or other manifestations of mitochondrial disease [2]. It may be used to assess the metabolic status of tissues in vivo or to monitor progression of the disease or treatment response non-invasively. Detailed information on brain or muscle bioenergetics is obtained by 31P MRS providing assays of adenosine 5′-triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), and the intracellular pH [3]. The scope of muscle studies may be widened by dynamic measurements during exercise or post-exercise recovery to extract relevant fluxes and turnover rates [4]. Alternatively, magnetization transfer (MT) techniques (i.e., inversion or saturation transfer) permit a direct determination of metabolic rates of enzyme reactions, such as the creatine kinase (CK) reaction [5]. Proton MRS of the brain provides access to the quantification of some key metabolites including Lac (the end product of failed OxPhos and, hence, a marker of anaerobic energy production), total creatine (tCr; serving as a marker of intact energy metabolism), N-acetylaspartate (NAA; which is generally believed to be absent in mature glia cells and thus a marker of neuronal integrity), myo-inositol (Ins; an osmolyte and, potentially, an astrocyte marker), glutamate (Glu; the main excitatory neurotransmitter), glutamine (Gln; the amination product of Glu in the astrocytes), and choline compounds (Cho; involved in membrane turnover) [3], [6].

Previous spectroscopy applications in MELAS were typically—though not exclusively—case reports including 14 studies with 1H MRS of the brain in 30 patients [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Absolute metabolite concentrations, however, are only available from 5 patients [15], [18], whereas the other studies are limited to qualitative data or metabolite ratios. Additional results from 31P MRS of the brain in five patients [2], [21], [22], [23] and of skeletal muscle in 13 patients [2], [18], [24], [25], [26], [27], [28] were also published. Consistent metabolic abnormalities are elevated Lac and decreased NAA as well as indications of impaired mitochondrial function in brain and muscle.

In this work, the primary focus is on MRS data from six retrospectively selected MELAS patients besides a brief review of the literature. The data include a previous case report [18] whereas the remaining cases have not yet been published. Our objective was to investigate metabolic disturbances in brain and muscle associated with MELAS on a quantitative level. A variety of techniques, both 1H and 31P MRS, was used for this purpose to provide examples of different experimental approaches for assessing and monitoring metabolic abnormality.

Section snippets

Patient and control group selection

During a period of 6 years, two male and four female patients (age range 9–41 years) referred to the University Hospital Münster were investigated with 1H or 31P MRS. The combined clinical and laboratory features led to the diagnosis of the full MELAS syndrome in patients 2 (m, 41 years), 3 (f, 11 years), 5 (f, 10 years), and 6 (f, 18 years). Additional genetic evidence (mtDNA point mutation at base pair 3243) was available in two of these cases (patients 3 and 5). Two unusual patients require

1H MRS

As a representative example, Fig. 1B shows a spectrum from a lesion in cortical GM recorded in patient 5. This patient bearing the 3243 mutation showed the full clinical picture of MELAS with headaches, stroke-like episodes, seizures, functional blindness of the left eye, and [Lac] elevation in CSF and plasma. A detailed case report was recently published elsewhere [18]. Findings at T2-weighted MRI included bilateral, symmetrical defects in the pallidae, multiple, mainly cortical lesions, and

Discussion

The involvement of brain and skeletal muscle in mitochondrial dysfunction accompanying MELAS is underlined on a quantitative level by MRS. Both 1H and 31P spectra provide well-established indicators of impaired energy metabolism, such as [Lac], [tCr], [Glc] and [PCr], [ADP], respectively. Additional indications of neuroaxonal damage or dysfunction are obtained from concentrations of NAA and Glu measured by cerebral 1H MRS.

The biochemical information extracted from 1H MRS can be brought into

Conclusions

Follow-up MRS studies, which are entirely non-invasive, are capable of providing quantitative markers of treatment response in vivo. This is particular useful in rare disorders such as MELAS in view of the limited number of patients available in single studies. Regarding substantial heterogeneity among individuals carrying the MELAS mutation, who seem to show a wide (and often puzzling) range of clinical phenotypes according to recent data [47], indications of a correlation of MRS data with

Acknowledgements

We thank Gerhard Schuierer for expert neuroradiologic advice, Bettina Pfleiderer for logistic support, and Stephan Liebig for help with the artwork. Financial support by the Deutsche Forschungsgemeinschaft (Mo 588/3-1) is gratefully acknowledged.

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