Neurocognitive Decline Following Radiotherapy: Mechanisms and Therapeutic Implications

Abstract

The brain undergoes ionizing radiation (IR) exposure in many clinical situations, particularly during radiotherapy for malignant brain tumors. Cranial radiation therapy is related with the hazard of long-term neurocognitive decline. The detrimental ionizing radiation effects on the brain closely correlate with age at treatment, and younger age associates with harsher deficiencies. Radiation has been shown to induce damage in several cell populations of the mouse brain. Indeed, brain exposure causes a dysfunction of the neurogenic niche due to alterations in the neuronal and supporting cell progenitor signaling environment, particularly in the hippocampus-a region of the brain critical to memory and cognition. Consequent deficiencies in rates of generation of new neurons, neural differentiation and apoptotic cell death, lead to neuronal deterioration and lasting repercussions on neurocognitive functions. Besides neural stem cells, mature neural cells and glial cells are recognized IR targets. We will review the current knowledge about radiation-induced damage in stem cells of the brain and discuss potential treatment interventions and therapy methods to prevent and mitigate radiation related cognitive decline.

Keywords: ionizing radiation; neural stem cells; neurocognitive effects; neurogenesis.

Figure 1

Potential mechanisms triggering radiation-induced cognitive impairment. Brain radiation injury is multifactorial and complex, involving dynamic interactions between multiple cell types. Brain irradiation may cause decline in oligodendrocytes and other glial cells, vascular damage, impaired hippocampal neurogenesis, altered function of adult neurons, and neuroinflammation caused by activated microglia. All these alterations likely contribute to the development of radiation-induced cognitive impairment (upper arrow). Selected strategies to prevent or minimize radiation-induced cognitive dysfunction are shown in the lower boxes, with data derived from both preclinical models and human studies.

Figure 2

Schematic illustration of reported adult neurogenesis sites in rodent, monkey and human brains. Neurogenesis takes place throughout life in the hippocampal dentate gyrus and the subventricular zone (SVZ) in rodents and is generally accepted to take place in adult monkey and human brains. The output of new neurons from the SVZ to the olfactory bulb is different between humans and other mammals, and humans exhibit very pronounced striatal adult neurogenesis compared to rodents and non-human primates (reviewed in [42]). A different number of neurogenic zones can be detected in adult rodents, monkeys and humans; hypothalamus and substantia nigra in rodents; amygdala, piriform cortex and inferior temporal cortex in monkeys; and striatum in humans. This figure is inspired by the Scalable Brain Atlas website and its 3-D Composer.