Abstract
BackgroundTwo studies using 31P-magnetic resonance spectroscopy (MRS) reported enhanced phosphocreatine (PCr) levels in normal appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but this finding could not be properly explained.Methodology/Principal FindingsWe performed 31P-MRS and 1H-MRS in the NAWM in 36 subjects, including 17 with progressive MS, 9 with benign MS, and 10 healthy controls. Compared to controls, PCr/β-ATP and PCr/total 31P ratios were significantly increased in subjects with progressive MS, but not with benign MS. There was no correlation between PCr ratios and the N-acetylaspartate/creatine ratio, suggesting that elevated PCr levels in NAWM were not secondary to axonal loss. In the central nervous system, PCr is degraded by creatine kinase B (CK-B), which in the white matter is confined to astrocytes. In homogenates of NAWM from 10 subjects with progressive MS and 10 controls without central nervous system disease, we measured CK-B levels with an ELISA, and measured its activity with an enzymatic assay kit. Compared to controls, both CK-B levels and activity were decreased in subjects with MS (22.41 versus 46.28 µg/ml; p = 0.0007, and 2.89 versus 7.76 U/l; p<0.0001).Conclusions/SignificanceOur results suggest that PCr metabolism in the NAWM in MS is impaired due to decreased CK-B levels. Our findings raise the possibility that a defective PCr metabolism in astrocytes might contribute to the degeneration of oligodendrocytes and axons in MS.
Highlights
Relapses and progression are the two basic clinical courses of multiple sclerosis (MS), which is traditionally viewed as a T-cell driven autoimmune disease against myelin
magnetic resonance spectroscopy (MRS) 1H MRS in the normal appearing white matter (NAWM) of the centrum semiovale showed a difference in NAA/Cr ratio between the three groups (p = 0.02), which was explained by a reduction in the progressive MS group compared to healthy controls (Dunn’s post test p,0.05) (Table 2)
31P MRS showed a significant difference among the 3 groups in the PCr/b-adenosine triphosphate (ATP) ratio (p = 0.02) and PCr/total 31P ratio (p = 0.03), which was explained by an increase in the progressive group compared to healthy controls (Dunn’s post test p,0.05) (Table 2)
Summary
Relapses and progression are the two basic clinical courses of multiple sclerosis (MS), which is traditionally viewed as a T-cell driven autoimmune disease against myelin. There is substantial evidence that inflammation plays a role in relapses, but whether this is a primary or secondary phenomenon remains a matter of controversy. The progressive phase of MS reflects an insidious axonal degeneration that is age related, and independent of relapses [4,5]. There is little evidence that inflammatory mechanisms play a primary role in this process as immunomodulatory drugs are ineffective in progressive MS. Two studies using 31P-magnetic resonance spectroscopy (MRS) reported enhanced phosphocreatine (PCr) levels in normal appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but this finding could not be properly explained
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