Neuroimaging of mitochondrial disease

doi:10.1016/j.mito.2008.05.003

Mitochondrion

Volume 8, Issues 5–6, December 2008, Pages 396-413

https://doi.org/10.1016/j.mito.2008.05.003 Get rights and content

Abstract

Mitochondrial disease represents a heterogeneous group of genetic disorders that require a variety of diagnostic tests for proper determination. Neuroimaging may play a significant role in diagnosis. The various modalities of nuclear magnetic resonance imaging (MRI) allow for multiple independent detection procedures that can give important anatomical and metabolic clues for diagnosis. The non-invasive nature of neuroimaging also allows for longitudinal studies. To date, no pathonmonic correlation between specific genetic defect and neuroimaging findings have been described. However, certain neuroimaging results can give important clues that a patient may have a mitochondrial disease. Conventional MRI may show deep gray structural abnormalities or stroke-like lesions that do not respect vascular territories. Chemical techniques such as proton magnetic resonance spectroscopy (MRS) may demonstrate high levels of lactate or succinate. When found, these results are suggestive of a mitochondrial disease. MRI and MRS studies may also show non-specific findings such as delayed myelination or non-specific leukodystrophy picture. However, in the context of other biochemical, structural, and clinical findings, even non-specific findings may support further diagnostic testing for potential mitochondrial disease. Once a diagnosis has been established, these non-invasive tools can also aid in following disease progression and evaluate the effects of therapeutic interventions.

Introduction

The interplay between nuclear and mitochondrial genomes creates a variety of presentations of mitochondrial disease that makes diagnosis difficult (Zeviani and Di Donato, 2004). Patients can have non-specific symptoms and even those patients with clinical findings compatible with known mitochondrial syndromes often have mixed etiologies. Therefore, although the recent advances in genetics have provided both the diagnostic tools and pathogenic insights into many mitochondrial disorders, the majority of patients suspected on clinical grounds to have a mitochondrial disease, require a combination of modalities for diagnostic confirmation (Hass et al., 2007, Thorburn et al., 2004).

In addition to the etiologic complexity of clinical diagnosis, the progressive and fluctuating course of mitochondrial disease can result in variable presentation. Due to this heterogeneity, it is not surprising that multiple systematic approaches to diagnosis exist; all of which use a combination of clinical, biochemical and structural criteria (Morava et al., 2006, Bernier et al., 2002, Wolf and Smeitnink, 2002, Nonaka, 2002, Nissenkorn et al., 2000, Walker et al., 1996). Most patients with mitochondrial disease demonstrate neurological symptoms and central nervous system findings that provide the foundation of diagnostic protocols. Although neurological symptoms often lead to the initial clinical referral, magnetic resonance imaging (MRI) plays an important role in interrogating the presence and pattern of central nervous system changes. As expected in this broad group of patients suspected to have a mitochondrial disease, MRI can reveal “signature” disease features, non-specific abnormalities, or a brain that appears structurally normal (Barragan-Campos et al., 2005, Munoz et al., 1999, Valanne et al., 1998). Metabolic and oxidative defects in mitochondrial disease can be further probed using magnetic resonance spectroscopy (MRS), which measures brain chemistry present in the millimolar (mM) range. Combined with clinical indices, these structural and biochemical probes can aid in identifying and characterizing a specific disorder. Due to the extremely safe and non-invasive nature of MRI and MRS, it is well suited to follow and evaluate disease progression, and to monitor therapeutic changes in these metabolic markers. The studies described below provide a detailed overview of the specific and non-specific changes in MRI and MRS shown to occur in mitochondrial disorders to date.

Prior to the availability of MRI, computed tomography (CT) was the mainstay for neuroimaging. Though MRI is more sensitive for detection of most pathology, CT can be useful for some pathological findings of mitochondrial disease, particularly in detecting calcification. With this in mind, we will concentrate on MRI and MRS and their use in mitochondrial disease.

Section snippets

Background of MRI

MRI is based on a physics phenomenon discovered in the 1930s, called nuclear magnetic resonance or NMR, which was initially developed as an analytical chemistry tool. NMR is based on the quantum mechanical property of spin possessed by protons and neutrons. Atomic nuclei with an odd number of protons have a net spin, a proportion of which, when placed in a magnetic field a subset of protons will align in one of two energy states. Slightly more nuclei will align with the field in the low energy

MRI: specific and non-specific changes in mitochondrial disease

Though most of the brain imaging abnormalities in patients with mitochondrial disease is non-specific, the pattern of these abnormalities can often be suggestive of metabolic disease. Non-specific global MRI abnormalities or structural changes of the brain are common in patients with mitochondrial disorders. The most common is a global delay in myelination pattern early in the course of the disease with “catch-up” as development continues (Dinopoulos et al., 2005, Munoz et al., 1999, Valanne et

Magnetic resonance spectroscopy

There have been a number of magnetic resonance techniques developed that complement conventional MRI and enhance sensitivity to pathological conditions within tissues. Magnetic spectroscopy (MRS) can provide valuable in vivo metabolic information to measure metabolites possessing resonating nuclei (hydrogen-1; ¹H: phosphorous-31; ³¹P: carbon-13; ¹³C) in the mM range. Typically ¹H MRS will involve suppression (within the acquisition sequence) of the water signal, which otherwise overwhelms the

Conclusions

Magnetic resonance imaging of mitochondrial disease demonstrates a variety of findings that can vary during the course of the clinical disease. Some well-described syndromes have MRI findings that can provide sensitivity for diagnosis. However, most mitochondrial diseases present with either non-specific findings or MRI images that can be completely normal. Many times however, when the combination of biochemical and clinical findings are compatible with a mitochondrial disorder, the

Acknowledgements

R.P.S. has received support from the Mitochondrial Research Guild at Children’s Hospital and Regional Medical Center, Seattle, WA. S.D.F. is supported in part by NIMH-1K01MH069848.

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Mini-reviewNeuroimaging of mitochondrial disease

Abstract

Introduction

Section snippets

Background of MRI

MRI: specific and non-specific changes in mitochondrial disease

Magnetic resonance spectroscopy

Conclusions

Acknowledgements

Mol. Genet. Metab.

Biochim. Biophys. Acta

Neurochem. Int.

J. Neurol. Sci.

J. Neurol. Sci.

Brain Dev.

Mol. Genet. Metab.

J. Pediatr.

Lancet

J. Neurol. Sci.

Biochim. Biophys. Acta

Cerebral lactic acidosis correlates with neurological impairment in MELAS

Neurology

Mitochondrial T9957C mutation in association with NAION and seizures but not MELAS

Ophthalmic Genet.

Structure and function of succinate dehydrogenase and fumarate reductase

Deep white matter pathologic features in watershed regions: a novel pattern of central nervous system involvement in MELAS

Arch. Neurol.

Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy

Cell. Mol. Biol. (Noisy-le-grand)

Detective brain energy metabolism shown by in vivo 31 P MR spectroscopy in 28 patients with mitochondrial cytopathies

J. Cereb. Blood Flow Metab.

Myo-neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome c-oxidase. A new mitochondrial multisystem disorder

Acta Neuropathol.

Mitochondrial disorders: analysis of their clinical and imaging characteristics

AJNR Am. J. Neuroradiol.

Brain magnetic resonance imaging findings in patients with mitochondrial cytopathies

Arch. Neurol.

Diagnostic criteria for respiratory chain disorders in adult and children

Neurology

Treatment monitoring of brain creatine deficiency syndromes: a 1H and 31P-MR spectroscopy study

AJNR Am. J. Neuroradiol.

Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance

AJNR Am. J. Neuroradiol.

1-(13)C glucose magnetic resonance spectroscopy of pediatric and adult brain disorders

NMR Biomed.

Succinate in dystrophic white matter a proton magnetic resonance spectroscopy finding characteristic for complex II deficiency

Ann. Neurol.

Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome

Brain Dev.

Detection of propan-1,2-diol in neonatal brain by in vivo proton magnetic resonance spectroscopy

Magn. Reson. Med.

MELAS syndrome: imaging and proton MR spectroscopic findings

AJNR Am. J. Neuroradiol.

Transient improvement of pyruvate metabolism after coenzyme Q therapy in Kearns–Sayre syndrome: MRS study

Yonsei Med. J.

MRI of the brain in the Kearns–Sayre syndrome: report of four cases and a review

Neuroradiology

N-Acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction

Dev. Neurosci.

MELAS: clinical and pathologic correlations with MRI, xenon/CT, and MR spectroscopy

Neurology

Short-term dichloroacetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders

Neurology

Brain MRI and proton MRS findings in infants and children with respiratory chain defects

Neuropediatrics

MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations

AJNR Am. J. Neuroradiol.

Evaluation of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes with magnetic resonance imaging and proton magnetic resonance spectroscopy

Chin. Med. Sci. J.

A case of incomplete Kearns–Sayre syndrome with a stroke like episode

Rinsho Shinkeigaku

Image formation in NMR by selective irradiative process

J. Phys. C Solid State Phys.

A mutation in the tRNA leu (UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies

Nature

Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion

Brain

Guidelines for the generalist on the diagnosis of mitochondrial disease

Pediatrics

Progressive neuronal degeneration of childhood with liver diseases (Alpers–Huttenlocher syndrome): a personal review

Mini-review
Neuroimaging of mitochondrial disease