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.
Highlights
EVALUATION OF PATIENT POPULATIONS FOR STUDYING RADIATION-INDUCED COGNITIVE IMPAIRMENT Several patient populations have been used to study radiationinduced cognitive impairment. These populations include (i) patients receiving prophylactic cranial irradiation (PCI) (Twijnstra et al, 1987; Laukkanen et al, 1988; Grosshans et al, 2008), (ii) patients with nasopharyngeal cancer (Cheung et al, 2000; Hsiao et al, 2010), (iii) patients with low-grade gliomas (Taphoorn et al, 1994; Klein et al, 2002), (iv) patients with benign nonparenchymal brain tumors (Gondi et al, 2011), and (v) patients with primary (Klein et al, 2002) or metastatic brain tumors (Nieder et al, 1999). The majority of these patients have (i) primary brain tumors treated with temozolomide and a variety of radiation therapy techniques or (ii) metastatic brain tumors treated with fractionated partial or whole brain irradiation (fWBI) or radiosurgery
Studying populations, who receive fWBI but do not have fast growing tumors in the brain, could provide important data on the role that radiation damage plays in generating cognitive impairment in primary and metastatic brain tumor patients
It is likely that the radiation-induced cognitive impairment measured in long term survivors of SCLC, nasopharyngeal cancer, lowgrade glioma, non-parenchymal tumors, primary brain tumors, and metastatic brain tumors is different because their diseases are treated differently
Summary
The only published report on patients with benign nonparenchymal brain tumors indicates that avoiding or lowering the dose to the hippocampus will reduce radiation-induced cognitive impairment (Gondi et al, 2011); the equivalent study has not been performed in animals. Atwood et al (2007) used a 7T MR scanner to demonstrate a potential relationship between radiation-induced changes in NAA/tCr, Glu + Gln/tCr, and mI/tCr concentrations in the rat brain after a 40 Gy total dose delivered in 5 Gy fractions, twice per week for 4 weeks and cognitive impairment measured by the novel object recognition test at 12 months after fWBI.
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