FLASH Radiotherapy and Cognitive Preservation: Mechanisms of Brain Protection After Whole-Brain Irradiation

FLASH radiotherapy (FLASH-rt) is an emerging cancer treatment approach that has shown promising normal-tissue-sparing effects in preclinical studies. This is particularly relevant for whole-brain irradiation, in which conventional radiotherapy (CONV-rt) can produce long-term cognitive deficits. This narrative review summarizes preclinical evidence on the cognitive-sparing effects of FLASH-rt following whole-brain irradiation and examines the neurobiological mechanisms that may underlie these effects. Recent studies indicate that FLASH-rt preserves declarative memory in rodents following both single-dose and fractionated irradiation. Compared with CONV-rt, FLASH-rt is associated with reduced oxidative stress, attenuated neuroinflammation, and preservation of neurogenesis and synaptic plasticity. Together, these findings suggest that FLASH-rt’s cognitive-sparing effects may result from coordinated attenuation of multiple pathways involved in radiation-induced brain injury. Understanding how these mechanisms interact may clarify FLASH-rt’s potential to reduce radiation-induced cognitive dysfunction while maintaining effective tumor control.