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, MK, 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 stage 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.

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…In the initial part of this study our goal was twofold. First, we wanted to confirm that, in our hands, the CPZ mouse model was behaving as previously described in terms of spatial and temporal distribution of lesions (37,(39)(40)(41)(42). Next, we evaluated the potential of T 2 -weighted MRI at high field strength (14.1 T) to detect cerebral lesions in CPZ mice.…”

“…However, no significant difference in nT 2 w signal values could be observed between W4 and W6 CPZ (P = 0.0562), despite the differences in underlying pathophysiological events observed at these two time points. In the CTRL group, nT 2 w signals significantly decreased over time (P = 0.0269), likely reflecting myelination of the corpus callosum in young adult mice (40,43).…”

“…5A, CPZ diet did not induce hyperintensities characteristic of demyelination and inflammation on T 2 -weighted MR images in the corpus callosum of CX 3 CR1 GFP/GFP mice. Quantitative analyses of the nT 2 w values from the corpus callosum showed that nT 2 w were significantly decreased at W4 in CPZ and CTRL CX 3 CR1 GFP/GFP , as well as in CTRL nontransgenic mice, reflecting normal myelination throughout development (40,43). In contrast to nontransgenic CPZ mice, however, no differences in T 2 w , and W6 + W6 recovery (purple) show a significant increase at W4 (96 ± 74% of W0, P = 0.0002) followed by a decrease at W6 and W6 + W6 recovery (P = 0.0194 and P = 0.0346, respectively).…”

“…We also demonstrated that only proinflammatory MPs up-regulate the enzyme PDK1, whereas astrocytes and OPCs did not. This result, combined with the lower levels of OPCs and the different temporal evolution of astrogliosis (maximum at W6), highly suggest that PDK1+ MPs are the major cell type contributing to the increased HP [1-13 C]lactate at W4 (40). Interestingly, we found a global decrease of PDH activity in the corpus callosum of nontransgenic CPZ mice at W4, but not in the thalamus, whereas LDH-A activity in both regions was unchanged by CPZ diet.…”

“…We chose to monitor CPZ mice at W4 and W6 of CPZ diet and after a subsequent period of 6 wk without CPZ because these three time points are characterized by different cellular events. At W4 of CPZ diet, cerebral lesions show a large recruitment and proliferation of MPs, which induce demyelination and can reach up to 50 times the density of microglia present under normal conditions (40). By W6 of CPZ diet, most of the MPs have disappeared and remyelination is ongoing despite continuous administration of the toxin (57,58).…”