Danielle A Simmons1, Frederick M Lartey2, Emil Schüler3, Marjan Rafat4, Gregory King3, Anna Kim3, Ryan Ko3, Sarah Semaan1, Selena Gonzalez1, Melissa Jenkins3, Pooja Pradhan3, Zion Shih3, Jinghui Wang3, Rie von Eyben3, Edward E Graves5, Peter G Maxim6, Frank M Longo7, Billy W Loo8. 1. Department of Neurology and Neurological Sciences, , Stanford University School of Medicine, United States. 2. Department of Radiation Oncology, Stanford University School of Medicine, United States; The Jackson Laboratory, Sacramento, United States. 3. Department of Radiation Oncology, Stanford University School of Medicine, United States. 4. Department of Radiation Oncology, Stanford University School of Medicine, United States; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, United States. 5. Department of Radiation Oncology, Stanford University School of Medicine, United States; Stanford Cancer Institute, Stanford University School of Medicine, United States. 6. Department of Radiation Oncology, Stanford University School of Medicine, United States; Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, United States. Electronic address: PMaxim@iu.edu. 7. Department of Neurology and Neurological Sciences, , Stanford University School of Medicine, United States. Electronic address: FLongo@Stanford.edu. 8. Department of Radiation Oncology, Stanford University School of Medicine, United States; Stanford Cancer Institute, Stanford University School of Medicine, United States. Electronic address: BWLoo@Stanford.edu.
Abstract
AIM: To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation. METHODS: We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay. RESULTS: At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3. CONCLUSION: Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors.
AIM: To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation. METHODS: We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay. RESULTS: At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3. CONCLUSION: Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors.
Authors: Barrett D Allen; Munjal M Acharya; Pierre Montay-Gruel; Patrik Goncalves Jorge; Claude Bailat; Benoît Petit; Marie-Catherine Vozenin; Charles Limoli Journal: Radiat Res Date: 2020-12-01 Impact factor: 2.841
Authors: Noora H Ba Sunbul; Wei Zhang; Ibrahim Oraiqat; Dale W Litzenberg; Kwok L Lam; Kyle Cuneo; Jean M Moran; Paul L Carson; Xueding Wang; Shaun D Clarke; Martha M Matuszak; Sara A Pozzi; Issam El Naqa Journal: Med Phys Date: 2021-09-08 Impact factor: 4.071
Authors: Pierre Montay-Gruel; Mineh Markarian; Barrett D Allen; Jabra D Baddour; Erich Giedzinski; Patrik Goncalves Jorge; Benoît Petit; Claude Bailat; Marie-Catherine Vozenin; Charles Limoli; Munjal M Acharya Journal: Radiat Res Date: 2020-12-01 Impact factor: 2.841
Authors: Dylan Yamabe Breitkreutz; Muhammad Shumail; Karl K Bush; Sami G Tantawi; Peter G Maxime; Billy W Loo Journal: Radiat Res Date: 2020-12-01 Impact factor: 2.841