Neuroimaging of mitochondrial disease

Division of Pediatric Neurology, Children's Hospital and Regional Medical Center/University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
Mitochondrion (Impact Factor: 3.25). 06/2008; 8(5-6):396-413. DOI: 10.1016/j.mito.2008.05.003
Source: PubMed


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.

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Available from: Russell P Saneto
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    • "The current strategy for diagnosis and classification of mitochondrial disorders includes a comprehensive and meticulous analysis of family history, clinical findings, biochemical and histopathological analyses, magnetic resonance imaging findings and molecular diagnostic testing (Graham, 2012). Among these, magnetic resonance imaging (MRI) is one of the easily accessible initial tools available to the clinician for interrogating the presence and pattern of central nervous system changes in patients with mitochondrial disorders (Bricout et al., 2014; Saneto et al., 2008). Apart from the structural imaging, the advanced imaging techniques also help to define the anatomical lesions, metabolism and hemodynamics in these patients (Haas & Dietrich, 2004; Finsterer, 2009a). "
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    ABSTRACT: Large studies analyzing magnetic resonance imaging correlates in different genotypes of mitochondrial disorders are far and few. This study sought to analyze the pattern of magnetic resonance imaging findings in a cohort of genetically characterized patients with mitochondrial disorders. The study cohort included 33 patients (age range 18months-50years, M:F - 0.9:1) with definite mitochondrial disorders seen over a period of 8yrs. (2006-2013). Their MR imaging findings were analyzed retrospectively. The patients were classified into three groups according to the genotype, Mitochondrial point mutations and deletions (n=21), SURF1 mutations (n=7) and POLG1 (n=5). The major findings included cerebellar atrophy (51.4%), cerebral atrophy (24.2%), signal changes in basal ganglia (45.7%), brainstem (34.2%) & white matter (18.1%) and stroke like lesions (25.7%). Spinal cord imaging showed signal changes in 4/6 patients. Analysis of the special sequences revealed, basal ganglia mineralization (7/22), lactate peak on magnetic resonance spectrometry (10/15), and diffusion restriction (6/22). Follow-up images in six patients showed that the findings are dynamic. Comparison of the magnetic resonance imaging findings in the three groups showed that cerebral atrophy and cerebellar atrophy, cortical signal changes and basal ganglia mineralization were seen mostly in patients with mitochondrial mutation. Brainstem signal changes with or without striatal lesions were characteristically noted in SURF1 group. There was no consistent imaging pattern in POLG1 group. Magnetic resonance imaging findings in mitochondrial disorders are heterogeneous. Definite differences were noted in the frequency of anatomical involvement in the three groups. Familiarity with the imaging findings in different genotypes of mitochondrial disorders along with careful analysis of the family history, clinical presentation, biochemical findings, histochemical and structural analysis will help the physician for targeted metabolic and genetic testing. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Sep 2015 · Mitochondrion
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    • "While some studies have shown that concentrations of brain lac can rise as a result of continuous neural stimulation[48], elevated brain lac is generally considered to reflect pathology induced from hypoxia or ischemia[49]or other metabolic crises[50]. However, in certain clinical situations (e.g., congenital mitochondrial disorders) in which mitochondrial function is compromised and cannot sustain ATP levels needed to fuel cellular processes[15], energy requirements are met (at least initially) through a compensatory upregulation of anaerobic glycolysis[17]which leads to elevated lac concentrations[16]. Based upon quantitative reports of metabolic pathology, similar physiological pressures are at play in aMCI all of which could lead to elevated lac in aMCI individuals further along across the disease progression. "
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    ABSTRACT: Mitochondrial dysfunction represents a central factor within the pathogenesis of the Alzheimer’s disease (AD) spectrum. We hypothesized that in vivo measurements of lactate (lac), a by-product of glycolysis, would correlate with functional impairment and measures of brain health in a cohort of 15 amnestic mild cognitive impairment (aMCI) individuals. Lac was quantified from the precuneus/posterior cingulate (PPC) using 2-dimensional J-resolved magnetic resonance spectroscopy (MRS). Additionally, standard behavioral and imaging markers of aMCI disease progression were acquired. PPC lac was negatively correlated with performance on the Wechsler logical memory tests and on the minimental state examination even after accounting for gray matter, cerebral spinal fluid volume, and age. No such relationships were observed between lac and performance on nonmemory tests. Significant negative relationships were also noted between PPC lac and hippocampal volume and PPC functional connectivity. Together, these results reveal that aMCI individuals with a greater disease progression have increased concentrations of PPC lac. Because lac is upregulated as a compensatory response to mitochondrial impairment, we propose that J-resolved MRS of lac is a noninvasive, surrogate biomarker of impaired metabolic function and would provide a useful means of tracking mitochondrial function during therapeutic trials targeting brain metabolism.
    Full-text · Article · Aug 2015
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    • "Since then, the diagnosis of Leigh syndrome has been based on symmetrical lesions in one or more areas of the central nervous system, including the basal ganglia, diencephalon, brainstem, cerebellum and spinal cord, on either post mortem examination or on neuroimaging [3,4]. Typically, the affected areas appear hypodense on computed tomography (CT) and show hyperintense signal on T2-weighted and hypointense signal on T1-weighted magnetic resonance imaging (MRI) [5,6]. "
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    ABSTRACT: Leigh syndrome is a progressive neurodegenerative disorder, associated with primary or secondary dysfunction of the mitochondrial oxidative phosphorylation. Despite the fact that Leigh syndrome is the most common phenotype of mitochondrial disorders in children, longitudinal natural history data is missing. This study was undertaken to assess the phenotypic and genotypic spectrum of patients with Leigh syndrome, characterise the clinical course and identify predictors of survival in a large cohort of patients. This is a retrospective study of patients with Leigh syndrome that have been followed at eight centers specialising in mitochondrial diseases in Europe; Gothenburg, Rotterdam, Helsinki, Copenhagen, Stockholm, Brussels, Bergen and Oulu. A total of 130 patients were included (78 males; 52 females), of whom 77 patients had identified pathogenic mutations. The median age of disease onset was 7 months, with 80.8% of patients presenting by the age of 2 years. The most common clinical features were abnormal motor findings, followed by abnormal ocular findings. Epileptic seizures were reported in 40% of patients. Approximately 44% of patients experienced acute exacerbations requiring hospitalisation during the previous year, mainly due to infections. The presence of pathological signs at birth and a history of epileptic seizures were associated with higher occurrence of acute exacerbations and/or relapses. Increased lactate in the cerebrospinal fluid was significantly correlated to a more severe disease course, characterised by early onset before 6 months of age, acute exacerbations and/or relapses, as well as brainstem involvement. 39% of patients had died by the age of 21 years, at a median age of 2.4 years. Disease onset before 6 months of age, failure to thrive, brainstem lesions on neuroimaging and intensive care treatment were significantly associated with poorer survival. This is a multicenter study performed in a large cohort of patients with Leigh syndrome. Our data help define the natural history of Leigh syndrome and identify novel predictors of disease severity and long-term prognosis.
    Full-text · Article · Apr 2014 · Orphanet Journal of Rare Diseases
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