title: Diffusion kurtosis imaging probes cortical alterations and white matter pathology following cuprizone induced demyelination and spontaneous remyelination.
abstract: Although MRI is the gold standard for the diagnosis and monitoring of multiple sclerosis (MS), current conventional MRI techniques often fail to detect cortical alterations and provide little information about gliosis, axonal damage and myelin status of lesioned areas. Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) provide sensitive and complementary measures of the neural tissue microstructure. Additionally, specific white matter tract integrity (WMTI) metrics modelling the diffusion in white matter were recently derived. In the current study we used the well-characterized cuprizone mouse model of central nervous system demyelination to assess the temporal evolution of diffusion tensor (DT), diffusion kurtosis tensor (DK) and WMTI-derived metrics following acute inflammatory demyelination and spontaneous remyelination. While DT-derived metrics were unable to detect cuprizone induced cortical alterations, the mean kurtosis (MK) and radial kurtosis (RK) were found decreased under cuprizone administration, as compared to age-matched controls, in both the motor and somatosensory cortices. The MK remained decreased in the motor cortices at the end of the recovery period, reflecting long lasting impairment of myelination. In white matter, DT, DK and WMTI-derived metrics enabled the detection of cuprizone induced changes differentially according to the stage and the severity of the lesion. More specifically, the MK, the RK and the axonal water fraction (AWF) were the most sensitive for the detection of cuprizone induced changes in the genu of the corpus callosum, a region less affected by cuprizone administration. Additionally, microgliosis was associated with an increase of MK and RK during the acute inflammatory demyelination phase. In regions undergoing severe demyelination, namely the body and splenium of the corpus callosum, DT-derived metrics, notably the mean diffusion (MD) and radial diffusion (RD), were among the best discriminators between cuprizone and control groups, hence highlighting their ability to detect both acute and long lasting changes. Interestingly, WMTI-derived metrics showed the aptitude to distinguish between the different stages of the disease. Both the intra-axonal diffusivity (Da) and the AWF were found to be decreased in the cuprizone treated group, Da specifically decreased during the acute inflammatory demyelinating phase whereas the AWF decrease was associated to the spontaneous remyelination and the recovery period. Altogether our results demonstrate that DKI is sensitive to alterations of cortical areas and provides, along with WMTI metrics, information that is complementary to DT-derived metrics for the characterization of demyelination in both white and grey matter and subsequent inflammatory processes associated with a demyelinating event.
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Guglielmetti
authors.affiliation: iMinds - Vision Lab, Department of Physics, University of Antwerp, Antwerp, Belgium; Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Veraart
authors.affiliation: StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Roelant
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: Z
authors.initials: Z
authors.lastname: Mai
authors.affiliation: Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Daans
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Van Audekerke
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Naeyaert
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Vanhoutte
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Delgado Y Palacios
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Praet
authors.affiliation: Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Fieremans
authors.affiliation: Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Ponsaerts
authors.affiliation: iMinds - Vision Lab, Department of Physics, University of Antwerp, Antwerp, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Sijbers
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium. Electronic address: annemie.vanderlinden@uantwerpen.be.
authors.forename: A
authors.initials: A
authors.lastname: Van der Linden
authors.affiliation: Bio-Imaging Lab, University of Antwerp, Antwerp, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Verhoye
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D002614:Chelating Agents / Q000633:toxicity; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D056324:Diffusion Tensor Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D066127:White Matter / Q000473:pathology*
chemical_list: D002614:Chelating Agents; D003471:Cuprizone
keywords: Cuprizone; Demyelination; Diffusion; Grey matter; Kurtosis; White matter