Radiation-induced cognitive impairment--from bench to bedside

Abstract

Approximately 100,000 patients per year in the United States with primary and metastatic brain tumor survive long enough (>6 months) to develop radiation-induced brain injury. Before 1970, the human brain was thought to be radioresistant; the acute central nervous system (CNS) syndrome occurs after single doses of ≥ 30 Gy, and white matter necrosis can occur at fractionated doses of ≥ 60 Gy. Although white matter necrosis is uncommon with modern radiation therapy techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become increasingly important, having profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenic mechanisms involved in radiation-induced cognitive impairment. Although reductions in hippocampal neurogenesis and hippocampal-dependent cognitive function have been observed in rodent models, it is important to recognize that other brain regions are affected; non-hippocampal-dependent reductions in cognitive function occur. Neuroinflammation is viewed as playing a major role in radiation-induced cognitive impairment. During the past 5 years, several preclinical studies have demonstrated that interventional therapies aimed at modulating neuroinflammation can prevent/ameliorate radiation-induced cognitive impairment independent of changes in neurogenesis. Translating these exciting preclinical findings to the clinic offers the promise of improving the quality of life in patients with brain tumors who receive radiation therapy.

Figures

Fig. 1.

Development of radiation-induced cognitive impairment as a function of time after young adult male Fischer 344 X Brown Norway rats were irradiated with a total 40 Gy dose of fractionated whole-brain irradiation (fWBI) delivered in 5 Gy fractions, twice/week for 4 weeks. Cognition was assessed using the novel object recognition (NOR) task. The sham-irradiated group value is the average of the NOR scores from unirradiated rats at all of the time points. In this rat model, cognitive impairment is both progressive and not significantly different from sham-irradiated rats until ∼6 months after fWBI, similar to what is observed in the clinic. ***P < 0.001.

Fig. 2.

Both PPAR agonists and RAS inhibitors prevent radiation-induced cognitive impairment in young adult male rats that received a total 40 Gy dose of fractionated whole-brain irradiation (fWBI) delivered in 5 Gy fractions, twice/week for 4 weeks, and then tested for cognition at 6–12 months postirradiation using the NOR task. Rats were administered, A, the PPARγ agonist, pioglitazone, before, during, and for 54 weeks post-fWBI; tested at 52 weeks; (B) the PPARα agonist, fenofibrate, before, during, and for 29 weeks post-fWBI; tested at 26 weeks; (C) the ARB, L158,809, before, during, and for 54 weeks post-fWBI; tested at 52 weeks; and (D) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at 26 weeks. *P < .05, **P < .01, ***P < .001 compared to sham-irradiated rats.