Molecular Pathways: Radiation-Induced Cognitive Impairment
Approximately 200,000/year in the US will receive partial or whole brain irradiation for the treatment of primary or metastatic brain cancer. Early and delayed radiation effects are transient and reversible with modern therapeutic standards; yet late radiation effects (≥6 months postirradiation) remain a significant risk, resulting in progressive cognitive impairment. These include functional deficits in memory, attention, and executive function that severely affect the patient's quality of life (QOL). The mechanisms underlying radiation-induced cognitive impairment remain ill defined. Classically, radiation-induced alterations in vascular and glial cell clonogenic populations were hypothesized to be responsible for radiation-induced brain injury. Recently, preclinical studies have focused on the hippocampus, one of two sites of adult neurogenesis within the brain, which plays an important role in learning and memory. Radiation ablates hippocampal neurogenesis, alters neuronal function, and induces neuroinflammation. Neuronal stem cells implanted into the hippocampus prevent the decrease in neurogenesis and improve cognition following irradiation. Clinically prescribed drugs, including PPAR α and γ agonists, as well as RAS blockers, prevent radiation-induced neuroinflammation and cognitive impairment independent of improved neurogenesis. Translating these exciting findings to the clinic offers the promise of improving the QOL of brain tumor patients who receive radiotherapy.