Development of diffusion-weighted MRI for the characterization of radio-induced neuropathological injuries in mouse model exposed to ionizing radiations

Whether for diagnostic or treatment purposes, the use of ionizing radiations can lead to detrimental and irreversible consequences especially for the developing brain. Furthermore, genetic factors are known to modulate the sensitivity and resilience of individuals to ionizing radiations. It is therefore necessary to develop and validate imaging biomarkers sensitive to the neuroanatomic and microstructural alterations induced by low to high doses of ionizing radiations. During this PhD thesis, I developed an integrated image acquisition and semi-automatic analysis approach based on anatomic and diffusion-weighted MRI, using in particular the S-Index, a novel signature of cellular density and applied it for the non-invasive characterization of radio-induced neuropathological injuries on the developing mice brain following various irradiation protocols. A first study was dedicated to the investigation of adult C57Bl/6 mice exposed in utero to a large (1 Gy) dose. A widespread brain atrophy was observed in association with changes in our diffusion parameters consistent with reductions in cellular density. We then investigated a model of radiosensitive mice (knock-out Xlf-/-) irradiated at low dose (100 mGy) at the embryonic (E14.5) or juvenile (PN10) stages. Larger volumetric and microstructural alterations were observed in the mice exposed at E14.5 compared to those exposed at PN10. Additionally, the deficiency in the Xlf gene (which is involved in the NHEJ pathway that repairs double-strand DNA breaks) could be associated with a ten-fold increase of the ionizing radiation's impact following in utero exposition. While few methodological improvements could be implemented in the near future, our approach could be of interest for translational research, in particular for the optimization of radiotherapy protocols or the study of other deleterious environmental or genetic factors on the developing brain. (author)