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.
"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 . In general, however, very little is known about the natural history of patients with PMD, either those with point mutations or gene duplications. "
[Show abstract][Hide abstract] 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.
Journal of the neurological sciences 08/2013; 335(1-2). DOI:10.1016/j.jns.2013.08.030 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We reported a 5-year-old boy with 18q(-) syndrome who showed typical magnetic resonance imaging (MRI) findings of high signal intensity on T2-weighted imaging, and a slightly high but lower than normal signal on T1-weighted imaging of the white matter. MR spectroscopy (MRS) revealed increased concentrations of creatine, myoinositol and choline with a normal N-acetylaspartate one. The cerebral white matter lesions observed on MRI in patients with 18q(-) syndrome have been considered to reflect hypomyelination due to a decrease in myelin basic protein so far, however, MRS suggested reactive astrocytic gliosis and accelerated myelin turnover, which are compatible with recent pathological reports of 18q(-) syndrome.
Brain & development 01/2013; 36(1). DOI:10.1016/j.braindev.2012.12.003 · 1.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A boy with Pelizaeus-Merzbacher disease underwent repeated evaluations by 3-Tesla (1)H-magnetic resonance spectroscopy (MRS). The patient showed overlap of the PLP1. Individuals selected as normal controls for (1)H-magnetic resonance spectroscopy consisted of healthy age-matched children. For (1)H-magnetic resonance spectroscopy, the center of a voxel was positioned in the right parietal lobe. (1)H-magnetic resonance spectroscopy was performed when the patient was 2, 6, 14, and 25 months old. γ-Aminobutyric acid concentration in early childhood was increased compared with that in normal controls. However, the γ-aminobutyric acid concentration in the Pelizaeus-Merzbacher disease patient was normalized at 14 and 25 months. No remarkable changes were observed in choline-containing compounds concentration at any time. These results suggest that the changes in metabolite concentrations during growth can reflect the pathological condition of Pelizaeus-Merzbacher disease. Furthermore, the lack of change in the choline-containing compounds concentration can be useful for differentiating Pelizaeus-Merzbacher disease from other white matter disorders.
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