Brain irradiation and long-term cognitive disability: Current concepts
Standard treatment of primary and metastatic brain tumors includes high dose megavoltage radiation to the cranial vault. About half of patients survive >6 months, many attain long term control or cure, but 50-90% of survivors overall exhibit disabling cognitive dysfunction. The radiation cognitive syndrome is poorly understood and there is no effective prevention or long-term treatment. Attention has primarily focused on mechanisms of disability appearing at six months to one year after radiotherapy. However, a range of studies have revealed that CNS alterations and dysfunction develop much earlier than 6 months following radiation exposure. This has prompted the recent hypothesis that relatively subtle early forms of radiation induced CNS damage may drive chronic pathophysiology leading to permanent cognitive decline. Within this perspective, the present review presents evidence of acute CNS irradiation triggered inflammation, and injury to neuronal lineages, accessory cells and their progenitors, and loss of supporting structure integrity. Moreover, injury related processes set in motion soon after intracranial irradiation may interact and synergize to alter the neuronal and supporting cell progenitor signaling environment in stem cell niches in the brain, and specifically in the hippocampus, a structure critical to memory and cognition. Changed niche conditions may cause a sustained decline in neurons and progressive deterioration of cognition. The concluding discussion addresses, (1) what further data is needed, and (2) potential treatment interventions, identified via recent findings on acute CNS radiation injury, that may reverse degenerative processes before they can cause permanent cognitive disability.