Differentiating unirradiated mice from those exposed to conventional or FLASH radiotherapy using MRI

Jansen, J.; Kimbler, A.; Drayson, O.; Lanz, B.; Mosso, J.; Grilj, V.; Petit, B.; Franco-Perez, J.; Simon, A.; Limoli, C. L.; Marie-catherine, V.; Stark, C.; Ballesteros Zebadua, P.

doi:10.1101/2025.02.01.636061

bioRxiv · 10.1101/2025.02.01.636061

Differentiating unirradiated mice from those exposed to conventional or FLASH radiotherapy using MRI

Jansen, J.·Kimbler, A.·Drayson, O.·Lanz, B.·Mosso, J.·Grilj, V.·Petit, B.·Franco-Perez, J.·Simon, A.·Limoli, C. L.·Marie-catherine, V.·Stark, C.·Ballesteros Zebadua, P.

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Abstract

Background and purposeThe FLASH effect expands the therapeutic ratio of tumor control to normal tissue toxicity observed after delivery of ultra-high (>100 Gy/s FLASH-RT) vs. conventional dose rate radiation (CONV-RT). In this first exploratory study, we assessed whether ex-vivo Magnetic Resonance Imaging (MRI) could reveal long-term differences after FLASH-RT and CONV-RT whole-brain irradiation. Materials and methodsFemale C57BL/6 mice were divided into three groups: control (non-irradiated), conventional (CONV-RT 0.1 Gy/s), and ultra-high dose rates (FLASH-RT 1 pulse, 5.5 x 106 Gy/s), and received 10 Gy of whole-brain irradiation in a single fraction at 10 weeks of age. Mice were evaluated by Novel Object Recognition cognitive testing at 10 months post-irradiation and were sampled at 13 months post-irradiation. Ex-vivo brains were imaged with a 14.1 Tesla/26 cm magnet with a multimodal MRI protocol, including T2-weighted TurboRare (T2W) and diffusion-weighted imaging (DWI) sequences. ResultsIn accordance with previous results, cognitive tests indicated that animals receiving CONV-RT exhibited a decline in cognitive function, while FLASH-RT performed similarly to the controls. MRI showed decreased hippocampal mean intensity in the CONV-RT mice compared to controls but not in the FLASH-RT group. Comparing CONV-RT to control, we found significant changes in multiple whole-brain diffusion metrics, including the mean Apparent Diffusion Coefficient (ADC) and Mean Apparent Propagator (MAP) metrics. By contrast, no significant diffusion changes were found between the FLASH-RT and control groups. In an exploratory analysis compared to controls, regional diffusion metrics were primarily altered in the basal forebrain and the insular cortex after CONV-RT, and after FLASH-RT, a trend reduction was also observed. ConclusionThis study presents initial evidence that MRI can uncover clear changes in the brain after CONV-RT but not after FLASH-RT. The MRI results aligned with the observed cognitive protection after FLASH-RT, indicating the potential use of MRI to analyze the FLASH response.

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Jansen, J., Kimbler, A., Drayson, O., Lanz, B., Mosso, J., Grilj, V., Petit, B., Franco-Perez, J., Simon, A., Limoli, C. L., Marie-catherine, V., Stark, C., Ballesteros Zebadua, P.. 2025-02-06. Differentiating unirradiated mice from those exposed to conventional or FLASH radiotherapy using MRI. https://doi.org/10.1101/2025.02.01.636061

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