phosphocreatine and Demyelinating-Diseases

Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS ((1) H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3 CL1/CX3 CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX3 CR1(+/-) C57BL/6 mice and wild type CX3 CR1(+/+) C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3 CR1(-/-) C57BL/6 mice. Second, we show that (1) H-MRS metabolite spectra are different when comparing cuprizone-treated CX3 CR1(-/-) mice showing mild demyelination with cuprizone-treated CX3 CR1(+/+) mice showing severe demyelination and demyelination-associated inflammation. Following cuprizone treatment, CX3 CR1(+/+) mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX3 CR1(-/-) mice only showed a decrease in tCho and tNAA concentrations. Therefore, (1) H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions.

Topics: Animals; Aspartic Acid; Brain Chemistry; Choline; Creatine; Cuprizone; Demyelinating Diseases; Dipeptides; Disease Models, Animal; Female; Gliosis; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Neuroimaging; Oligodendroglia; Phosphocreatine; Proton Magnetic Resonance Spectroscopy

We report of a woman aged 52 years born to consanguineous parents and seeking treatment for progressive dementia and delusion. Neurologic examination revealed dementia and emotional instability, indifference, and confabulation. There was also mild spasticity of the bilateral lower limbs. MRI revealed diffuse white matter hyperintensity on T2-weighted images accompanied by hypointense areas on fluid-attenuated inversion recovery images. A homozygous missense mutation was identified in EIF2B5.

Topics: Adult; Age of Onset; Brain; Creatine; Demyelinating Diseases; DNA Mutational Analysis; Eukaryotic Initiation Factor-2B; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Mutation, Missense; Phosphocreatine; Sequence Analysis, DNA

Proton magnetic-resonance spectroscopy (PMRS) was used to measure the levels of inositol/myoinositol (Ins), choline, creatine/phosphocreatine (Cr), glutamine/glutamate (Glx/Glx1), N-acetylaspartate (NAA), gamma-aminobutyric acid (GABA) and lipids were measured in the foci of demyelinization in the brains of 59 patients with multiple sclerosis (MS). Magnetic-resonance imaging was performed during a single investigation. A control group comprised 20 healthy individuals. PMRS revealed significant alterations in the levels of metabolite in all the patients as compared with the controls: decreases in NAA by 23-52%, in Cr by 12-21%, in choline by 15-26%; increases in Ins by 51-63%; as well as the appearance of lipids (up to 100%). In MS, there were reduction in NAA/Cr, NAA/choline, and NAA/choline/Cr ratios by 12-53; 10-19; and 57-82%, respectively. As compared with the remitting MS, secondary-progressive MS showed decreases in the content of NAA by 23-25%, NAA/(choline + Cr) by 48-54% and increases in the levels of Ins and lipids by 50-76%. In remitting MS, there was a strong correlation between the NAA/Cr ratio and the volume brain lesion. It is concluded that PMRS evaluated the extent, pattern and activity of demyelinization (by the levels of Ins, NAA, Cr, lipids) and the intensity of cerebral atrophy (by NAA levels, NAA/Cr ratio). The findings testify that there are neurochemical differences between remitting and secondary-progressive MS.

Topics: Adolescent; Adult; Aspartic Acid; Brain; Choline; Creatine; Demyelinating Diseases; Female; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Inositol; Magnetic Resonance Spectroscopy; Male; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Phosphocreatine; Severity of Illness Index

Adrenoleukodystrophy (ALD) is characterised by wide phenotypic variation, and there is no marker to predict the onset of cerebral demyelination. The indications for therapeutic approaches depend largely on the onset of cerebral demyelination.. To evaluate the brain spectroscopic pattern in normal-appearing white matter (NAWM) in patients with various phenotypes of ALD to determine if these abnormalities could be of useful prognostic value.. Spectroscopic imaging acquisition mode (MRSI, 16 x 16 voxels) was performed in 20 patients with ALD, including 7 neurologically asymptomatic patients without detectable demyelination on MRI, 3 patients with early signs of cerebral demyelination, 8 patients with adrenomyeloneuropathy (AMN) and 2 patients with cerebral ALD who had previously undergone bone marrow transplantation. Controls were 22 healthy subjects. In all patients, four voxels entirely located in the juxtaventricular NAWM were studied. The ratios NAA/Cho, NAA/ CPC and Cho/CPC for the four ROIs were measured in the patient population and compared with control values. Results. In spite of a large distribution of ratios, the statistical tests did not show any significant difference between the ratios within NAWM in the patient population compared with control values. Means of ratios in the left posterior (LP) voxel compared normal subjects were (a) in neurologically asymptomatic ALD patients (n = 7) 2.27 +/- 0.63 for NAA/CPC, 2.21 +/- 0.75 for NAA/ Cho, 1.06 +/- 0.28 for Cho/CPC, (b) in patients with early signs of demyelination (n = 3) 3.43 +/- 0.85 for NAA/ CPC, 2.47 +/- 0.32 for NAA/Cho, 1.37 +/- 0.16 for Cho/CPC and (c) in AMN patients (n = 8) 1.47 +/- 0.53 for NAA/CPC, 2.17 +/- 1.58 for NAA/ Cho, 0.83 +/- 0.32 for Cho/CPC. Conclusions. The study did not show significant differences in metabolite ratios between patients and controls. The large distribution of results precludes the possibility of detecting small variations. Part of this distribution can be due to the CSI method. Longitudinal spectroscopic studies, preferentially using monovoxel spectroscopy, are clearly needed.

Topics: Adolescent; Adrenoleukodystrophy; Adult; Age Factors; Brain; Child; Choline; Data Interpretation, Statistical; Demyelinating Diseases; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Phenotype; Phosphocreatine; Prognosis; Sensitivity and Specificity

We have performed localised proton magnetic resonance spectroscopy (MRS) of the brain on four patients with X-linked adrenoleukodystrophy (X-ALD). The spectrum is characterised at the beginning of the disease by a decrease in N-acetylaspartate and phosphocreatine-creatine content. Choline is strongly increased, and lactate can be detected in some cases. A proton signal from the CH2 groups borne by free intracellular very long chain fatty acids can also be observed. Later in the disease, the levels of all metabolites, in particular NAA, decrease significantly. The progression of neurometabolism documented by MRS correlates well with MRI and clinical progression on follow-up study. In one case, the metabolic profile recorded by proton MRS was abnormal before any change occurred on MRI. Proton MRS of the brain might be the method of choice for monitoring patients with X-ALD, to screen presumed cases and to study the effects of treatment.

Topics: Adolescent; Adrenoleukodystrophy; Adult; Aspartic Acid; Brain; Child; Creatine; Demyelinating Diseases; Fatty Acids; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Phosphocreatine; Sex Chromosome Aberrations; X Chromosome

Magnetization transfer imaging (MT) and localized proton spectroscopy (1H-MRS) were utilized in the evaluation of lesions (high signal abnormalities on T2-weighted images) and normal-appearing white matter (NAWM) in multiple sclerosis (MS). Eleven patients with a clinical diagnosis of MS were independently evaluated with both 1H-MRS and MT. The magnetization transfer ratio (MTR) of lesions was compared with the relative concentration of N-acetyl-aspartate (NAA) and a composite peak at 2.1 to 2.6 ppm termed "marker peaks." The MTR of white matter lesions in the MS patients was markedly decreased (6-34%; normal approximately 42%), and correlated well with increase in the marker peaks region (0.94-3.89). There was no correlation between the relative concentration of NAA and MTR. Increased resonance peaks in the 2.1 to 2.6 ppm range and marked decreases in MTR may be a relatively specific indicators of demyelination.

Topics: Adolescent; Adult; Aged; Aspartic Acid; Brain; Choline; Cohort Studies; Creatine; Demyelinating Diseases; Humans; Hydrogen; Image Enhancement; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Multiple Sclerosis; Phosphocreatine; Signal Processing, Computer-Assisted

Osmotic injury induced by rapid correction of severe chronic hyponatremia has been implicated in the development of central pontine myelinolysis. Organic osmolytes known previously as "idiogenic osmoles" accumulate intracellularly to protect cells from osmotic injury. We investigated the changes of these organic osmolytes as well as electrolytes in the brain during the induction and correction of chronic hyponatremia. Using 1H-nuclear magnetic resonance spectroscopy and HPLC, we found that in rats with chronic hyponatremia (3 d, serum sodium = 109 +/- 3 meq/liter), brain concentrations of myoinositol (41%), glycerophosphorylcholine (45%), phosphocreatine/creatine (60%), glutamate (53%), glutamine (45%), and taurine (37%) were all significantly decreased compared with control values (percentage control value shown, all P less than 0.01). The contribution of measured organic osmolytes and electrolytes to the total brain osmolality change was 23 and 72%, respectively. With rapid correction by 5% NaCl infusion, significant brain dehydration and elevation of brain Na and Cl levels above the normal range occurred at 24 h. These changes were not seen with slow correction by water deprivation. Reaccumulation of most organic osmolytes except glycerophosphorylcholine is delayed during the correction of hyponatremia and is independent of the correction rate of serum sodium. It is concluded that: most of the change of brain osmolality in chronic hyponatremia can be accounted by the changes in organic osmolytes and brain electrolytes; and rapid correction of hyponatremia is associated with an overshoot of brain sodium and chloride levels along with a low organic osmolyte level. The high cerebral ion concentrations in the absence of adequate concentrations of organic osmolytes may be relevant to the development of central pontine myelinolysis.

Topics: Animals; Body Water; Brain; Chronic Disease; Creatinine; Demyelinating Diseases; Electrolytes; Hyponatremia; Magnetic Resonance Spectroscopy; Male; Osmolar Concentration; Phosphocreatine; Pons; Rats; Rats, Inbred Strains