Increased N-acetylaspartate in model mouse of Pelizaeus-Merzbacher disease

Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Journal of Magnetic Resonance Imaging (Impact Factor: 3.21). 02/2012; 35(2):418-25. DOI: 10.1002/jmri.22817
Source: PubMed


To evaluate the N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) biochemical pathways in the brain of myelin synthesis-deficient (msd) mouse, a model of Pelizaeus-Merzbacher disease (PMD).
We performed magnetic resonance imaging and proton magnetic resonance spectroscopy (¹H-MRS) of the thalamus for msd and wildtype mice with a 7.0 T magnet. NAA and NAAG were independently measured by high-performance liquid chromatography (HPLC). Immunohistochemical analysis using anti-Mbp, Gfap, Ng2, and NeuN antibodies were also performed.
¹H-MRS in msd mice revealed increased total NAA (tNAA, NAAþNAAG), creatine, glutamine, and glutamate and decreased choline (Cho). HPLC analysis revealed increases of both NAA and NAAG in the msd brains. Histologically, the msd brains revealed hypomyelination and astrogliosis. Oligodendrocyte progenitor cells and neurons were normal in number in the thalamus wherein ¹H-MRS was obtained.
The evidence suggests that the neurochemical derangement in the msd mice may be a primary increase of NAA resulting in a secondary increase of NAAG. Increased tNAA with decreased Cho detectable on ¹H-MRS may be an important marker for PMD, and might be used to distinguish it from more common neurological disorders that have decreased tNAA.

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    • "The measurement of NAA and NAAG by HPLC was performed as described previously (Reynolds et al., 2005;Takanashi et al., 2012). Brain tissue was homogenized with 10 times the volume of 0.1 M perchloric acid. "
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    Full-text · Article · Feb 2014 · The International Journal of Neuropsychopharmacology
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    • "e l s e v i e r . c o m / l o c a t e / j n s that has a point mutation in PLP [20]. In general, however, very little is known about the natural history of patients with PMD, either those with point mutations or gene duplications. "
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    ABSTRACT: To determine whether quantitative measure of magnetic resonance imaging data from patients with the inherited leukodystrophy, Pelizaeus-Merzbacher disease (PMD) correlates with clinical severity or progression. In our current work we have analyzed the clinical phenotypes and MRI scans of 51 male patients with PMD and 10 female carriers for whom the PLP1 genotype had been determined. In addition, we developed a 32-point functional disability scoring (FDS) system for PMD, and validated it for inter-rater reliability. Using conventional T1- and T2-weighted MRI images of the whole brain, we measured white matter and total brain volume (WMV and TBV), inter-caudate ratio (ICR), and corpus callosum area. There was a significant positive correlation of FDS with white matter fraction (WMV/TBV) and corpus callosum area. Also, when applying a median split based on FDS, patients with lower FDS showed reduced white matter fraction and corpus callosum area, and increased ICR compared to patients with relatively higher FDS, regardless of age. Although this patient population is heterogeneous, with multiple genetic and molecular mechanisms causing PMD, these data imply that white matter atrophy is a major pathological determinant of the clinical disability in most patients. Development of reliable non-invasive quantitative biomarkers of disease activity would be useful not only for following the natural history of the disease, but also raising the potential for evaluating future therapies.
    Full-text · Article · Aug 2013 · Journal of the neurological sciences
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    No preview · Article · Jan 2013 · Brain & development
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