ID #923 Impact of proton FLASH delivery technique on memory preservation and microglial response following whole-brain irradiation
Devin Miles, Daniel Sforza, Chanel Hutchison, Mina Akter, Xingyu Chen, Yanbo Tang, Nicole Tan, Matthew Ladra, Xun Jia, Heng Li, Eric Raabe, Robyn Gartrell, Sahaja AcharyaAbstract
Background
Neurocognitive impairment is a significant late effect of radiation therapy (RT) in children with brain tumors. Ultra-high dose rate (>40 Gy/s) radiotherapy (FLASH-RT) has been shown to mitigate neurocognitive deficits in mice. We implemented varying proton FLASH-RT delivery strategies to evaluate the impact of delivery technique on memory and microglial response after whole-brain irradiation (WBRT).
Methods
C57BL/6 mice at 7-8 weeks of age received 10 Gy proton WBRT using four transmission-beam techniques via Hitachi ProBEAT synchrotron with online small-animal CBCT guidance: (1) single-spill pencil beam scanning (PBS) (SS; 3 × 3 spots,); (2) multi-spill PBS (MS; 3 × 3 spots, ∼2 s inter-spot delay); (3) passive scattering (PS; single spot); and (4) clinical dose-rate delivery (CONV; 3 × 3 spots). Each technique included 24–28 mice with equal sex distribution and compared to unirradiated (SHAM) controls. Per-mouse dose and dose-rate were calculated from time-resolved transmission monitor chamber data. Dose-rate metrics included field dose rate (FDR), pencil-beam scanning dose rate (PBSDR), and dose-averaged dose rate (DADR). Memory was assessed at 6 weeks post-RT using novel object recognition. Discrimination index (DI) was calculated as (novel − familiar)/total exploration time. Higher DI indicates better memory. Specimens were taken from 3 female mice/treatment group 6 weeks post-treatment to evaluate using hashtag single cell RNA-sequencing (scRNA-seq).
Results
By FDR/PBSDR, FLASH-RT was achieved only with SS and PS; by DADR, all techniques met FLASH-RT because inter-pulse times are excluded. At 6 weeks, DI was higher for SS (p = 0.021), MS (p = 0.008), and PS (p < 0.001) versus CONV, which did not differ from SHAM (p = 0.510). DI did not differ among SS, MS, and PS. ScRNA-seq data showed differential microglial activation at 6 weeks post treatment.
Conclusion
FLASH-RT spared memory irrespective of proton delivery technique and differentially affected microglial activation compared to CONV WBRT in healthy mice.