TY - JOUR
T1 - Cuprizone-induced demyelination and demyelination-associated inflammation result in different proton magnetic resonance metabolite spectra
AU - Praet, Jelle
AU - Orije, Jasmien
AU - Kara, Firat
AU - Guglielmetti, Caroline
AU - Santermans, Eva
AU - Daans, Jasmijn
AU - Hens, Niel
AU - Verhoye, Marleen
AU - Berneman, Zwi
AU - Ponsaerts, Peter
AU - Van der Linden, Annemie
N1 - Publisher Copyright:
© 2015 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (1H-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 CX3CL1/CX3CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX3CR1+/- C57BL/6 mice and wild type CX3CR1+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3CR1-/- C57BL/6 mice. Second, we show that 1H-MRS metabolite spectra are different when comparing cuprizone-treated CX3CR1-/- mice showing mild demyelination with cuprizone-treated CX3CR1+/+ mice showing severe demyelination and demyelination-associated inflammation. Following cuprizone treatment, CX3CR1+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX3CR1-/- mice only showed a decrease in tCho and tNAA concentrations. Therefore, 1H-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.
AB - Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (1H-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 CX3CL1/CX3CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX3CR1+/- C57BL/6 mice and wild type CX3CR1+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3CR1-/- C57BL/6 mice. Second, we show that 1H-MRS metabolite spectra are different when comparing cuprizone-treated CX3CR1-/- mice showing mild demyelination with cuprizone-treated CX3CR1+/+ mice showing severe demyelination and demyelination-associated inflammation. Following cuprizone treatment, CX3CR1+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX3CR1-/- mice only showed a decrease in tCho and tNAA concentrations. Therefore, 1H-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.
KW - CXCR1
KW - Cuprizone
KW - Demyelination
KW - MRI
KW - Spectroscopy
UR - http://www.scopus.com/inward/record.url?scp=84925269837&partnerID=8YFLogxK
U2 - 10.1002/nbm.3277
DO - 10.1002/nbm.3277
M3 - Article
C2 - 25802215
AN - SCOPUS:84925269837
SN - 0952-3480
VL - 28
SP - 505
EP - 513
JO - NMR in biomedicine
JF - NMR in biomedicine
IS - 4
ER -