Radiation-induced cognitive toxicity: pathophysiology and interventions to reduce toxicity in adults

Abstract

Radiotherapy is ubiquitous in the treatment of patients with both primary brain tumors as well as disease which is metastatic to the brain. This therapy is not without cost, however, as cognitive decline is frequently associated with cranial radiation, particularly with whole brain radiotherapy (WBRT). The precise mechanisms responsible for radiation-induced morbidity remain incompletely understood and continue to be an active area of ongoing research. In this article, we review the hypothetical means by which cranial radiation induces cognitive decline as well as potential therapeutic approaches to prevent, minimize, or reverse treatment-induced cognitive deterioration. We additionally review advances in imaging modalities that can potentially be used to identify site-specific radiation-induced anatomic or functional changes in the brain and their correlation with clinical outcomes.

Fig. 1

Selected proposed mechanisms of radiation-induced neurocognitive dysfunction. (A) Pro-inflammatory changes following radiotherapy result in an increase in the numbers of microglia which produce TNF-α and IL-6. This contributes to an ongoing inflammatory state and alteration in the microenvironment, which preferentially drive differentiation of neural precursors to an astrocytic lineage. (B) Radiation disrupts the vascular niche of the neural precursors and additionally leads to ischemia and toxic neuroexcitation among mature neurons. (C) Radiation exposure reduces the number of dendritic spines on mature neurons, which in turn disrupts synaptic efficiency.