Molecular pathways: radiation-induced cognitive impairment

Abstract

Each year, approximately 200,000 patients in the United States 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 risks include functional deficits in memory, attention, and executive function that severely affect the patient's quality of life. The mechanisms underlying radiation-induced cognitive impairment remain ill defined. Classically, radiation-induced alterations in vascular and neuroinflammatory 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 after irradiation. Clinically prescribed drugs, including PPARα and PPARγ 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 quality of life of brain tumor patients who receive radiotherapy.

FIGURE 1

A. Potential mechanisms underlying radiation-induced cognitive impairment. Radiation-induced cognitive impairment likely involves dynamic interactions between multiple cell types in the brain. Brain irradiation causes changes in the vasculature, glial cell populations, hippocampal neurogenesis, neuronal function, and elicits neuroinflammation. All of these pathways likely contribute to the development of radiation-induced cognitive impairment. B. Potential therapeutic intervetions to prevent radiation-induced cognitive impairment. Preclinical models suggest that radiation-induced cognitive impairment can be prevented/ameliorated by targeting neurogenesis or inflammation. Neuronal stem cell transplants to the hippocampus can restore neurogenesis; improving cognitive function. PPAR agonists and RAS blockers prevent neuroinflammation and radiation-induced cogitive impairment independent of changes in neurogenesis.

FIGURE 1

A. Potential mechanisms underlying radiation-induced cognitive impairment. Radiation-induced cognitive impairment likely involves dynamic interactions between multiple cell types in the brain. Brain irradiation causes changes in the vasculature, glial cell populations, hippocampal neurogenesis, neuronal function, and elicits neuroinflammation. All of these pathways likely contribute to the development of radiation-induced cognitive impairment. B. Potential therapeutic intervetions to prevent radiation-induced cognitive impairment. Preclinical models suggest that radiation-induced cognitive impairment can be prevented/ameliorated by targeting neurogenesis or inflammation. Neuronal stem cell transplants to the hippocampus can restore neurogenesis; improving cognitive function. PPAR agonists and RAS blockers prevent neuroinflammation and radiation-induced cogitive impairment independent of changes in neurogenesis.