title: Cuprizone-induced demyelination and demyelination-associated inflammation result in different proton magnetic resonance metabolite spectra.
abstract: 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.
authors: Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium; Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium; Bio-Imaging Laboratory, University of Antwerp, Antwerp, Belgium.
authors: Jelle
authors: J
authors: Praet
authors: Jasmien
authors: J
authors: Orije
authors: Firat
authors: F
authors: Kara
authors: Caroline
authors: C
authors: Guglielmetti
authors: Eva
authors: E
authors: Santermans
authors: Jasmijn
authors: J
authors: Daans
authors: Niel
authors: N
authors: Hens
authors: Marleen
authors: M
authors: Verhoye
authors: Zwi
authors: Z
authors: Berneman
authors: Peter
authors: P
authors: Ponsaerts
authors: Annemie
authors: A
authors: Van der Linden
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000032:analysis; D001923:Brain Chemistry; D002794:Choline / Q000032:analysis; D003401:Creatine / Q000032:analysis; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000175:diagnosis / Q000473:pathology*; D004151:Dipeptides / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000139:chemically induced / Q000175:diagnosis / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059906:Neuroimaging / Q000379:methods*; D009836:Oligodendroglia / Q000473:pathology; D010725:Phosphocreatine / Q000032:analysis; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D004151:Dipeptides; D010725:Phosphocreatine; C027172:isospaglumic acid; D001224:Aspartic Acid; D003471:Cuprizone; C000179:N-acetylaspartate; D003401:Creatine; D002794:Choline
keywords: CX3CR1; MRI; cuprizone; demyelination; spectroscopy