Reduced Creatine Kinase B Activity in Multiple Sclerosis Normal Appearing White Matter

BACKGROUND: Two studies using (31)P-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 FINDINGS: We performed (31)P-MRS and (1)H-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 (31)P 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/SIGNIFICANCE: Our 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.