Radiation-induced brain injury: A review

Abstract

Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their integration at clinically relevant doses and schedules. Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects.

Keywords: brain injury; hippocampal changes; metastatic brain tumor; pathogenesis; radiation-induced.

FIGURE 1

Symptoms and timeline for the development of radiation-induced brain injury in patients treated with fWBI.

FIGURE 2

The percentage of patients developing radiation-induced cognitive impairment as a function of time after fWBI. Adapted from Nieder et al. (1999).

FIGURE 3

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 fWBI delivered as 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.

FIGURE 4

Diffusion tensor image of a rat brain color-coded to show the predominant direction of diffusion in various brain regions; blue indicates diffusion between anterior (A) and posterior (P), red indicates flow between left (L) and right (R), and green indicates flow between superior (S) and inferior (I). Adapted from Robbins et al. (2012).

FIGURE 5

[¹⁸F]FDG-PET scans of cerebral glucose metabolism 9 months after fWBI of young adult male non-human primates. Upper panel: post-fWBI < Pre-fWBI. Blue areas in the cuneate cortex and prefrontal cortex exhibited less metabolic activity in scans obtained 9 months after fWBI than in scans obtained prior to fWBI. Lower panel: post-fWBI > Pre-fWBI: the red areas in the cerebellum and thalamus exhibited greater metabolic activity in scans obtained 9 months after fWBI than in scans obtained prior to fWBI. The color bar is the degree of intensity difference shown as a scale of t values with P <0.001. Adapted from Robbins et al. (2012).

FIGURE 6

Both RAS inhibitors and PPAR agonists prevent radiation-induced cognitive impairment in young adult male rats that received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, twice/week for 4 weeks, and then tested for cognition at 6–12 months post-irradiation using the NOR task. Rats were administered, (A) the ARB, L-158,809 before, during, and for 54 weeks post-fWBI; tested at 52 weeks, (B) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at 26 weeks, (C) the PPARγ agonist, pioglitazone, before, during, and for 54 weeks post-fWBI; tested at 52 weeks, and (D) the PPARα agonist, fenofibrate, before, during, and for 29 weeks post-fWBI; tested at 26 weeks. *P <0.05, **P <0.01, ***P <0.001 compared to sham-irradiated rats.