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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 CX 3 CL1/CX 3 CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX 3 CR1 +/−  C57BL/6 mice and wild type CX 3 CR1 +/+  C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX 3 CR1 −/−  C57BL/6 mice. Second, we show that  1 H‐MRS metabolite spectra are different when comparing cuprizone‐treated CX 3 CR1 −/−  mice showing mild demyelination with cuprizone‐treated CX 3 CR1 +/+  mice showing severe demyelination and demyelination‐associated inflammation. Following cuprizone treatment, CX 3 CR1 +/+  mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX 3 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. Copyright © 2015 John Wiley & Sons, Ltd.

Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra