Cognitive and imaging differences after proton and photon whole brain irradiation in a preclinical model.

PURPOSE Compared to photon radiation therapy (X-CRT), proton cranial radiotherapy (P-CRT) offers potential advantages in limiting radiation-induced sequalae in the treatment of pediatric brain tumors. This study aims to identify cognitive, functional MR and PET imaging markers and molecular differences between the radiation modalities. METHODS Juvenile rats received a single faction of 10 Gy (RBE weighted dose) delivered with 6 MV X-CRT or at the mid-spread out Bragg peak of a 100 MeV P-CRT beam. At 3, 6, and 12 months post-CRT executive function was measured using 5-choice serial reaction time task. At ∼12 months post-CRT, animals were imaged with 18F-FDG PET imaging followed by functional ex-vivo MRI and stained for markers of neuroinflammation. RESULTS Irradiated animals had cognitive impairment with higher number of omissions, lower incorrect and premature responses compared to sham (P≤0.05). X-CRT animals' accuracy was less than sham (P≤0.001). No significant difference in rates of cognitive change were found between the radiation modalities. At 12 months post-CRT, glucose metabolism was significantly higher than sham in X-CRT (P=0.04) but not P-CRT. Using diffusion tensor imaging, P-CRT brains were found to have higher white matter volume and fiber lengths compared to sham (P<0.03). Only X-CRT animals had higher apparent diffusion coefficient values compared to sham (P=0.04). P-CRT animals had more connectomic changes compared to X-CRT. Correlative analysis identified several imaging features with cognitive performance. Furthermore, microgliosis (P<0.05), astrogliosis (P<0.01), and myelin thinning (P<0.05) were observed in both radiation modalities, with X-CRT showing slightly more inflammation. CONCLUSIONS Both P-CRT and X-CRT lead to neurocognitive changes compared to sham. While no significant difference was observed in neuroinflammation between the irradiated groups, differences were found in late-term glucose metabolism and brain connectome. Our results indicate that despite RBE weighting of the proton dose there are still differential effects which warrants further investigation.