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Radiation-induced brain injury: A review

Radiation-induced brain injury: A review REVIEW ARTICLE published: 19 July 2012 doi: 10.3389/fonc.2012.00073 -- -- | | 1,2 1,2 1,2 1,2 Dana Greene-Schloesser , Mike E. Robbins * , Ann M. Peiffer , Edward G. Shaw , 2,3 1,2 Kenneth T. Wheeler and Michael D. Chan Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA Brain Tumor Center of Excellence, Wake Forest School of Medicine, Winston-Salem, NC, USA Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA Edited by: Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive Michael L. Freeman, Vanderbilt long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the University School of Medicine, USA human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after Reviewed by: single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although Michael L. Freeman, Vanderbilt white matter necrosis is uncommon with modern techniques, functional deficits, includ- University School of Medicine, USA Eddy S. Yang, Comprehensive Cancer ing progressive impairments in memory, attention, and executive function have become Center, University of Alabama- important, because they have profound effects on quality of life. Preclinical studies have Birmingham School of Medicine, provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. USA Given its central role in memory and neurogenesis, the majority of these studies have *Correspondence: focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to Mike E. Robbins, Department of Radiation Oncology, Wake Forest several hippocampal changes including neuroinflammation and a marked reduction in neu- School of Medicine, Medical Center rogenesis. These data have been interpreted to suggest that shielding the hippocampus Boulevard, Room 412C NRC, will prevent clinical radiation-induced cognitive impairment. However, this interpretation Mail Box #571059, Winston-Salem, may be overly simplistic. Studies using older rodents, that more closely match the adult NC 27157, USA. e-mail: mrobbins@wakehealth.edu human brain tumor population, indicate that, unlike pediatric and young adult rats, older -| Dana Greene-Schloesser and Mike E. rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Robbins have contributed equally to Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of this article. demyelination and/or white matter necrosis similar to what is observed clinically, suggest- ing 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 RADIATION-INDUCED BRAIN INJURY solely to a reduction in the proliferating capacity of glial (van den Maazen et al., 1993) or vascular endothelial (Calvo et al., Radiation-induced brain injury is often observed after fraction- ated partial or whole brain irradiation (fWBI); the syndrome 1988) cells. The loss of either of these cell types could ulti- mately produce white matter necrosis, but the loss of glial cells includes both anatomic and functional deficits. Based on the time of clinical expression (Figure 1), radiation-induced brain injury was thought to cause necrosis earlier than the loss of vascular endothelial cells. However, there is a growing awareness that is described in terms of acute, early delayed, and late delayed injury (Tofilon and Fike, 2000). Acute brain injury, expressed patients receiving fWBI can have significant cognitive impair- in days to weeks after irradiation, is rare with current radia- ment at >6 months post-irradiation even when they do not have tion therapy techniques. Early delayed brain injury occurs 1–6 detectable anatomic abnormalities (Sundgren and Cao, 2009). The months post-irradiation and can involve transient demyelina- impact of cognitive impairment on a patient’s quality of life (QOL) tion with somnolence. Although both of these early injuries can is now recognized as second only to survival in clinical trials result in severe reactions, they are normally reversible and resolve (Frost and Sloan, 2002). spontaneously. In contrast, late delayed brain injury, character- ized histopathologically by vascular abnormalities, demyelination, THE VASCULAR HYPOTHESIS OF LATE DELAYED and ultimately white matter necrosis (Schultheiss and Stephens, RADIATION-INDUCED BRAIN INJURY 1992), is usually observed >6 months post-irradiation; these late Proponents of the vascular hypothesis of late radiation-induced delayed injuries have been viewed as irreversible and progressive. brain injury argue that vascular damage leads to ischemia and sec- Classically, late radiation-induced brain injury was viewed as due ondarily to white matter necrosis. In support of this hypothesis, www.frontiersin.org July 2012 | Volume 2 | Article 73 | 1 “fonc-02-00073” — 2012/7/18 — 14:49 — page1—#1 Greene-Schloesser et al. Radiation-induced brain injury THE PARENCHYMAL HYPOTHESIS OF RADIATION-INDUCED BRAIN INJURY OLIGODENDROCYTES The parenchymal hypothesis of radiation-induced brain injury initially focused on the oligodendrocyte that is required for the formation of myelin sheaths. The key cell for generating mature oligodendrocytes is the oligodendrocyte type-2 astrocyte (O-2A) progenitor cell that loses its reproductive capacity after WBI in the rat (Raff et al., 1983). It has been hypothesized that radiation- induced loss of O-2A progenitor cells leads to a failure to replace oligodendrocytes that ultimately results in demyelination and white matter necrosis. Although the oligodendrocyte population in young adult rats has been reported to be depleted within 24 h after single WBI doses of ≥3 Gy and total fWBI doses of ≥4.5 Gy (Bellinzona et al., 1996; Shinohara et al., 1997; Kurita et al., 2001), FIGURE 1 Symptoms and timeline for the development of no change in the number of myelinated axons, the thickness of radiation-induced brain injury in patients treated with fWBI. myelin sheaths, and the cross-sectional area of myelinated axons has been measured in cognitively impaired rats 12 months after a total fWBI dose of 40 Gy delivered twice a week for 4 weeks to a large amount of data has described radiation-induced vascular middle-aged rats (Shi et al., 2009). Further, although the kinetics structural changes, including vessel wall thickening, vessel dila- of oligodendrocyte depletion is consistent with an early transient tion, and endothelial cell nuclear enlargement (Calvo et al., 1988; demyelination, it is inconsistent with the late onset of white mat- Reinhold et al., 1990; Schultheiss and Stephens, 1992). Quantita- ter necrosis (Hornsey et al., 1981). Thus, the relationship between tive studies in irradiated rat brains have also demonstrated time- radiation damage to oligodendrocytes and late radiation-induced and dose-dependent reductions in the number of endothelial cell brain injury is still unclear. nuclei, blood vessel density, and blood vessel length (Reinhold et al., 1990; Brown et al., 2007). Moreover, white matter necro- ASTROCYTES sis occurs in boron neutron capture studies where nearly all of These cells constitute approximately 50% of the total glial cell the radiation damage is to the vasculature (Morris et al., 1996). population in the brain and outnumber the neurons four to A recent study in rodents has shown that capillary rarefaction one in higher mammals (Hansson, 1988). Once viewed as play- and tissue hypoxia increased in all regions of the hippocampus ing a mere supportive role, astrocytes are now recognized as 2 months after fWBI (Warrington et al., 2011a). Paradoxically, a heterogeneous class of cells that perform diverse functions, these investigators also showed that low ambient oxygen levels including modulation of synaptic transmission and secretion of were able to restore the brain microvascular density (Warring- neurotrophic factors such as basic fibroblast growth factor to ton et al., 2011a,b) and reverse cognitive impairment (Warrington promote neurogenesis (Song et al., 2002; Seth and Koul, 2008). et al., 2012). Other studies have shown that (i) alterations of the Astrocytes have been shown to protect endothelial cells and blood–brain barrier (BBB) likely due to an imbalance in the lev- neurons from oxidative injury (Wilson, 1997). Also, juxtacrine els of the matrix metalloproteinase-2 and the metalloproteinase-2 signaling between astrocytes and endothelial cells is critical for tissue inhibitor, (ii) degradation of collagen type IV, an extracellu- generation and maintenance of a functional BBB, the vascular lar matrix component of the blood vessel basement membrane structure that restricts entry of blood-borne elements into the (Lee et al., 2012), and (iii) changes in the mRNA and protein brain (Janzer and Raff, 1987). In response to injury, astrocytes expression of VEGF, Ang-1, Tie-2, and Ang-2 (Lee et al., 2011) undergo proliferation, exhibit hypertrophic nuclei/cell bodies, occur after clinically relevant single and fWBI doses. In a recent and show increased expression of glial fibrillary acidic protein study, primary cultured mouse fetal neural stem cells injected (GFAP; Seifert et al., 2006; Yuan et al., 2006; Seth and Koul, into the tail vein after each of four 5 Gy fractions differenti- 2008; Wilson et al., 2009; Zhou et al., 2011). These reactive ated into both brain endothelial cells and a variety of brain astrocytes secrete a host of pro-inflammatory mediators such as cells; this restored the radiation-induced decrease in both cerebral cyclooxygenase (Cox)-2 and the intercellular adhesion molecule blood flow and cognitive function (Joo et al., 2012). In contrast, (ICAM)-1, which may aid the infiltration of leukocytes into the radiation-induced necrosis has been reported in the absence of brain via BBB breakdown (Kyrkanides et al., 1999; Yuan et al., vascular changes (Schultheiss and Stephens, 1992). Also the PPARγ 2006; Wilson et al., 2009; Zhou et al., 2011). Irradiating the rat agonist, pioglitazone, and the ACE inhibitor, ramipril, that prevent and mouse brain increases GFAP protein levels, both acutely radiation-induced cognitive impairment in the rat (Zhao et al., (24 h) and chronically (4–5 months; Chiang et al., 1993; Hong 2007a,b; Lee et al., 2012) do not reverse the reduction in vascular et al., 1995). Conditioned medium from irradiated microglial cells density and length that occurs after fWBI (Brown, unpublished has been shown to induce astrogliosis which might contribute to data). Consequently, late radiation-induced brain injury cannot be radiation-induced edema (Hwang et al., 2006). However, the exact solely due to vascular damage despite the large amount of evidence role of astrocytes in the overall pathogenesis of late radiation- supporting this hypothesis. induced brain injury is still unclear, but they likely contribute by Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 2 “fonc-02-00073” — 2012/7/18 — 14:49 — page2—#2 Greene-Schloesser et al. Radiation-induced brain injury interacting with both vascular and other parenchymal elements in 1993), and neuronal gene expression (Noel et al., 1998; Rosi the brain. et al., 2008). For example, irradiating the rodent brain with single and fractionated doses produces changes in (i) neuronal MICROGLIA receptor expression of the immediate-early gene activity-regulated These immune cells represent about 12% of the total brain cytoskeleton-associated protein (Arc) (Rosi et al., 2008), (ii) N - cells (Gebicke-Haerter, 2001). In an uninjured brain, microglia methyl-D-aspartic acid (NMDA) receptor subunits (Shi et al., actively monitor the microenvironment to ensure that homeostasis 2006; Machida et al., 2010), (iii) glutaminergic transmission is maintained (Stoll and Jander, 1999). Microglia express neu- (Rohde et al., 1979; Machida et al., 2010), and (iv) hippocam- rotrophins that selectively regulate (i) microglial function, (ii) pal long-term potentiation (LTP; Snyder et al., 2001; Vlkolinsky secretion of neurotrophic factors which promote neuronal sur- et al., 2008); all are important for synaptic plasticity and cognition. vival, and (iii) proliferation (Elkabes et al., 1996). After injury, Interestingly, these changes can occur in the absence of alterations microglia become activated, a process characterized by rounding in the total number of mature neurons, the number of myelinated of the cell body, retraction of cell processes, proliferation, and axons, the thickness of myelin sheaths, and/or the cross-sectional increased production of reactive oxygen species (ROS), cytokines, area of myelinated axons following fWBI (Shi et al., 2008). Thus, and chemokines that mediate neuroinflammation (Stoll and Jan- subtle cellular and/or molecular changes in the neurons themselves der, 1999; Gebicke-Haerter, 2001; Pocock and Liddle, 2001; or subtle changes in the association/communication between neu- Kim and de Vellis, 2005). rons and astrocytes must play an as yet unidentified role in late Although microglial activation plays an important role in radiation-induced cognitive impairment. phagocytosis of dead cells, sustained activation is thought to contribute to a chronic inflammatory state in the brain (Gebicke- THE DYNAMIC INTERACTIONS BETWEEN MULTIPLE CELL Haerter, 2001; Joo et al., 2012). Tissue culture studies have demon- TYPES HYPOTHESIS strated that irradiating activated microglia leads to a marked Because no single cell or tissue associated with either the vas- increase in expression of the pro-inflammatory genes TNFα,IL- cular or parenchymal hypotheses can fully explain late delayed 1β, IL-6, and Cox-2, and the chemokines, MCP-1 and ICAM-1 radiation-induced brain injury, including cognitive impairment, (Chiang et al., 1993; Kyrkanides et al., 1999, 2002; Hwang et al., radiation-induced late effects are now hypothesized to occur due 2006; Lee et al., 2010). Rodent studies have also detected (i) an to dynamic interactions between the multiple cell types in the increase in pro-inflammatory mediators within hours after irra- brain (Tofilon and Fike, 2000). Vascular endothelial cells, oligo- diating the brain (Chiang et al., 1997; Kyrkanides et al., 2002; Lee dendrocytes, astrocytes, microglia, and neurons, are now viewed et al., 2010), and (ii) an increase in the percentage of activated not as passive bystanders that merely die from radiation dam- microglia in the brain during the latent period before the expres- age, but rather as active participants in an orchestrated response sion of late radiation-induced brain injury (Mildenberger et al., to radiation injury that, theoretically, allows one to change the 1990; Chiang et al., 1997; Monje et al., 2003). Rodent studies response/outcome by intervening at numerous points in the and analysis of human brain tissue also suggest that microglial process to prevent or ameliorate the development of late radiation- activation may be associated with decreased hippocampal neuro- induced brain injury, including cognitive impairment. It is likely genesis and cognitive function (Monje et al., 2002, 2007; Raber that the successful unraveling of this puzzle will require the detec- et al., 2004). Anti-inflammatory agents such as ramipril and tion of subtle molecular, cellular, and microanatomic changes indomethacin reduce the number of activated microglia in the hip- in the brain that will clearly challenge basic science and clinical pocampus and/or perirhinal cortex and prevent radiation-induced investigators over the next decade. cognitive impairment in rodents (Monje et al., 2003; Lee et al., 2012). However, the anti-inflammatory agent, L-158, 809, has COGNITIVE IMPAIRMENT IN BRAIN TUMOR SURVIVORS no effect on microglial activation, but still prevents radiation- AFTER fWBI induced cognitive impairment (Robbins et al., 2009; Conner et al., 2010). Finally, orthotopic injections of fetal neuronal stem cells Radiation-induced cognitive impairment, including dementia, is (NSC) that form new neurons without affecting the number of reported to occur in up to 50–90% of adult brain tumor patients activated microglia reverse radiation-induced cognitive impair- who survive >6 months post-irradiation (Crossen et al., 1994; ment in rodents (Acharya et al., 2009, 2011). Thus, the exact Giovagnoli and Boiardi, 1994; Johannesen et al., 2003; Meyers and role that activated microglia play in generating radiation-induced Brown, 2006). This cognitive impairment is marked by decreased brain injury, including cognitive impairment, is still an open verbal memory, spatial memory, attention, and novel problem- question. solving ability (Hochberg and Slotnick, 1980; Twijnstra et al., 1987; Laukkanen et al., 1988; Roman and Sperduto, 1995). Nieder NEURONS et al. (1999) described significant cognitive impairment in 49% of Once considered a radioresistant population because they no patients at 2 years after treatment with fWBI; the incidence and longer could divide, neurons have now been shown to respond severity continued to rise over time (Figure 2). Chang et al. (2009) negatively to radiation. Studies have demonstrated radiation- documented a detectable cognitive impairment at 4 months after induced changes in hippocampal cellular activity (Gangloff and fWBI compared to patients treated with radiosurgery. Moreover, Haley, 1960; Bassant and Court, 1978), synaptic efficiency/spike radiation-induced cognitive impairment occasionally progresses generation (Bassant and Court, 1978; Pellmar and Lepinski, to dementia where patients experience progressive memory loss, www.frontiersin.org July 2012 | Volume 2 | Article 73 | 3 “fonc-02-00073” — 2012/7/18 — 14:49 — page3—#3 Greene-Schloesser et al. Radiation-induced brain injury assessing radiation-induced cognitive impairment (Herman et al., 2003; Kondziolka et al., 2005). The MMSE (i) does not avoid memorized learning from repeat testing, (ii) is biased against patients with lower educational backgrounds, and (iii) is rel- atively insensitive to the subtle changes in function caused by brain radiotherapy. To overcome these problems, recent cognitive assessments have focused on the specific domains that are most affected by brain irradiation (Klein et al., 2002; Shaw et al., 2006; Chang et al., 2009). Using intense neurocognitive assessments on primary and metastatic brain tumor patients has been criticized because many of their tumors recur leading to a general decline in health and death. As such, patients are generally less willing to partici- pate in intense cognitive testing as their health deteriorates, and the utility of the results from those that do participate is ques- tionable. Recently, RTOG study formulated a battery of tests | that focuses on the cognitive domains known to be affected FIGURE 2 The percentage of patients developing radiation-induced cognitive impairment as a function of time after fWBI. Adapted from by brain irradiation, including memory, verbal fluency, visual Nieder et al. (1999). motor speed, and executive function (Table 1); the estimated time of completion is ∼30 min. In recent trials, this battery of cognitive tests appears to overcome this major obstacle to ataxia, and urinary incontinence (Vigliani et al., 1999). Radiation- assessing radiation-induced cognitive impairment in brain tumor induced dementia is a rare occurrence with fraction sizes <3Gy patients. (DeAngelis et al., 1989; Klein et al., 2002). However, patients who survive >2 years after fWBI have a continually increasing risk of EVALUATION OF PATIENT POPULATIONS FOR STUDYING developing dementia over time (Scott et al., 1999). Importantly, all RADIATION-INDUCED COGNITIVE IMPAIRMENT of these late sequelae can be seen in the absence of radiographic Several patient populations have been used to study radiation- or clinical evidence of demyelination or white matter necrosis induced cognitive impairment. These populations include (Dropcho, 1991; Shaw et al., 2006). (i) patients receiving prophylactic cranial irradiation (PCI) (Twi- In spite of the relative rarity of progressing to frank dementia, jnstra et al., 1987; Laukkanen et al., 1988; Grosshans et al., 2008), radiation-induced cognitive impairment has significant effects on (ii) patients with nasopharyngeal cancer (Cheung et al., 2000; QOL. The majority of >6 month survivors of partial or whole Hsiao et al., 2010), (iii) patients with low-grade gliomas (Taphoorn brain irradiation have a symptom cluster consisting of fatigue, et al., 1994; Klein et al., 2002), (iv) patients with benign non- changes in mood, and cognitive dysfunction (Gleason et al, 2007). parenchymal brain tumors (Gondi et al., 2011), and (v) patients Results of neurocognitive testing in a phase III clinical trial (PCI with primary (Klein et al., 2002) or metastatic brain tumors P120-9801) showed a significant correlation between performance (Nieder et al., 1999). The majority of these patients have (i) pri- on the Functional Assessment of Cancer Therapy-Brain Specific mary brain tumors treated with temozolomide and a variety (FACT-Br) test and a patient’s QOL as measured by the ability of radiation therapy techniques or (ii) metastatic brain tumors to perform daily living activities (Li et al., 2008). In the Nieder treated with fWBI or radiosurgery. In general, about 50–70% et al. (1999) study, 20% of patients treated with fWBI had a >10% of these patients survive long enough (>6 months) to develop decline in Karnofsky Performance Status due to radiation-induced radiation-induced cognitive impairment that affects their QOL. cognitive impairment. Furthermore, brain tumor patients are sur- Therefore, this is the population that presents the greatest chal- viving longer due to improved radiation therapy techniques and lenge to the radiation oncologist. Nevertheless, it is also the systemic therapies (Stupp et al., 2005; Cochran et al., 2012), so population with the greatest number of confounding factors (e.g., the patient population experiencing radiation-induced cognitive short life spans with declining health, tumor effects on brain impairment is growing rapidly. Consequently, the search for (i) regions associated with cognition, prior treatment of systemic biomarkers to identify patients who will/will not develop cog- disease with a variety of chemotherapeutic agents, concurrent nitive impairment after fWBI and (ii) therapeutic strategies to treatment with chemotherapy, steroids, and neurotrophic drugs) prevent/ameliorate radiation-induced cognitive impairment have that, by themselves, can affect cognition. Therefore, studying pop- become very important. ulations, who receive fWBI but do not have fast growing tumors in the brain, could provide important data on the role that radiation ASSESSING RADIATION-INDUCED COGNITIVE damage plays in generating cognitive impairment in primary and IMPAIRMENT IN THE CLINIC metastatic brain tumor patients. The assessment of radiation-induced cognitive impairment in the SMALL CELL LUNG CANCER PATIENTS clinic has evolved over time. The mini-mental status examina- tion (MMSE), a test for global cognitive function which has been The NCI published a study on 15 SCLC patients who were validated in other cognitive disorders, is relatively insensitive for long-term survivors after PCI and found that 12 of these Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 4 “fonc-02-00073” — 2012/7/18 — 14:49 — page4—#4 Greene-Schloesser et al. Radiation-induced brain injury Table 1 | Neurocognitive batteries used in modern prospective clinical trials. Trial Intelligence Perception/psychomotor speed Memory Attention/executive function EORTC Dutch adult reading test Line bisection test Working memory task Stroop color word test Facial recognition test Visual verbal learning test Categoric word fluency test Judgment of line orientation Concept shifting test Letter-digit substitution RTOG 0614 COWA Trail-making A Hopkins verbal learning test Trail-making B RTOG 0933 N/A N/A Hopkins verbal learning test N/A One card learning test International shopping list test MDACC N/A N/A Hopkins verbal learning test N/A CCOP 97100 COWA Trail-making A California verbal learning test Trail-making B Rey Osterrieth complex figure Digit span exhibited abnormalities on neuropsychiatric testing, while seven LOW-GRADE GLIOMA PATIENTS performed below the normal range on the MMSE test (John- In a seminal publication by Klein et al. (2002), cognitive outcomes son et al., 1990). However, in a larger study of 69 SCLC of patients with low-grade glioma were compared to both patients patients who received PCI, a substantial portion of the patients with indolent lymphomas that had no CNS disease and healthy exhibited cognitive impairments prior to PCI, and multivari- controls. The radiotherapy fields used in this study generally did ate analysis could not identify any significant cognitive differ- not include the entire brain. This analysis revealed that low-grade ences before and after PCI (Grosshans et al., 2008). Finally, in gliomas, anti-epileptic medications, and radiotherapy could each another recent study, patients who received PCI had a detectable produce cognitive impairment; cognition was most affected if frac- decline in verbal memory just 6–8 weeks after completion of tions >2 Gy were used. Consequently, radiation-induced cognitive PCI (Welzel et al., 2008). Thus, the radiation-induced cogni- data from low-grade glioma patients are also not likely to provide tive impairment data from SCLC patients who receive PCI information relevant to the majority of primary and metastatic is confusing at best, probably because these patients received brain tumor patients. Shaw et al published results of a random- chemotherapy and/or larger radiation fractions that are not typ- ized trial in 200 adult low-grade glioma patients who received ical of those used to treat primary and metastatic brain tumor either 50.4 Gy or 64.8 Gy at 1.8 Gy per fraction to partial brain patients. treatment fields (Shaw et al, 2002). This is the only known modern primary brain tumor study in which patients were randomized to NASOPHARYNGEAL CANCER PATIENTS receive low- versus high dose-radiation. There were no differences Survivors of nasopharyngeal cancer offer another opportu- in survival outcomes by dose. However, the incidence of radiation nity to measure radiation-induced cognitive impairment in the necrosis (i.e., grade 3, 4 or 5 late brain toxicity) However, the 5- absence of a brain tumor. Patients treated for nasopharyn- year actuarial incidence of radiation necrosis (i.e., grade 3, 4 or 5 geal cancer routinely have high doses of radiation delivered late brain toxicity) was 10% in patients receiving 64.8 Gy versus to the bilateral temporal lobes because of the need to treat 5% for those given 50.4 Gy. the superior retropharyngeal lymph nodes. These patients have ∼70% chance of long-term survival, and thus, the poten- BENIGN NON-PARENCHYMAL BRAIN TUMOR PATIENTS tial for development of radiation-induced cognitive impair- Arguably, the ideal populations for determining the radiation ment, primarily due to damage to the temporal lobes. Che- tolerance of various brain regions are the patients with benign ung et al. (2000) reported that temporal lobe necrosis pre- non-parenchymal brain tumors such as meningiomas, pituitary dicted a worsening of cognitive impairment in 50 irradiated tumors, and schwannomas. These tumors generally do not affect nasopharyngeal cancer patients who were followed longitudi- cognition and are not treated with chemotherapy. Patients with nally with neuropsychological testing. Recently, Hsiao et al. (2010) these tumors have life expectancies long enough after fWBI to demonstrated that nasopharyngeal cancer patients treated with experience radiation-induced cognitive impairment. Finally, the intensity-modulated radiotherapy (IMRT) had a worse cogni- results of these human studies could be compared to the results tive outcome if >10% of their temporal lobe volume received of preclinical animal studies on radiation-induced brain injury, a total fractionated dose of >60 Gy than patients who received including cognitive impairment, all of which have been performed <60 Gy. in animals that have no brain tumors or neurological diseases www.frontiersin.org July 2012 | Volume 2 | Article 73 | 5 “fonc-02-00073” — 2012/7/18 — 14:49 — page5—#5 Greene-Schloesser et al. Radiation-induced brain injury (Lamproglou et al., 1995; Yoneoka et al., 1999; Raber et al., 2004; needed to study this significant side effect of brain tumor radio- Rola et al., 2004). Such a comparison could greatly facilitate the therapy. Given that radiation-induced cognitive impairment can development of molecular, cellular, or imaging biomarkers of the occur in the absence of radiographic evidence of gross anatomi- onset and progression of radiation-induced cognitive impairment cal changes, X-ray computed tomography (CT), T1/T2 magnetic or interventions that could be successfully translated to the clinic. resonance imaging (MRI), and ultrasound techniques are not Presently, the only published report on patients with benign non- likely to provide information relevant to the onset and progres- parenchymal brain tumors indicates that avoiding or lowering the sion of radiation-induced cognitive impairment. However, both dose to the hippocampus will reduce radiation-induced cognitive MRI and positron emission tomography (PET) have the ability impairment (Gondi et al., 2011); the equivalent study has not been to interrogate metabolic, physiologic, and functional properties performed in animals. of the brain. MRI utilizes magnetic fields to generate informa- From the above discussion, it is distinctly possible that tion by exciting the protons in hydrogen atoms and monitoring the molecular, cellular, and microanatomic events that lead them as they relax. Depending on the pulse sequence, differ- to radiation-induced cognitive impairment are different for ences in the magnetic susceptibility properties of tissues can be SCLC, nasopharyngeal cancer, low-grade glioma, benign non- exploited to probe various molecular, cellular, microanatomic, and parenchymal brain tumor, primary brain tumor, and metastatic physiologic properties of normal and tumor tissues. Magnetic res- brain tumor patients. Consequently, (i) identifying biomarkers of onance spectroscopy (MRS) utilizes an MR scanner to identify and the onset and progression of radiation-induced cognitive impair- quantify metabolites that reflect both the cellular properties and ment and (ii) developing therapeutic strategies to prevent or environmental conditions in specific regions of normal and tumor ameliorate radiation-induced cognitive impairment is likely to be tissues. PET utilizes radioligands that contain an atom that emits challenging for both basic scientists and physicians. a positron to interrogate the metabolic, receptor, physiologic, and functional properties of normal and tumor tissue. Theoretically, THE NEUROANATOMICAL TARGET THEORY OF these three non-invasive techniques have the ability to identify RADIATION-INDUCED COGNITIVE IMPAIRMENT biomarkers of the onset and progression of radiation-induced The target structures and dose thresholds for the development cognitive impairment. of radiation-induced cognitive impairment are of current clinical interest. Prior studies have suggested that partial brain irradia- NON-INVASIVE VASCULAR BIOMARKERS OF tion may not cause the same degree of cognitive impairment as RADIATION-INDUCED COGNITIVE IMPAIRMENT WBI (Armstrong et al., 1995; Torres et al., 2003). This observa- Vascular injury has been hypothesized to play a critical role tion could be explained by hypothesizing that there are specific in the development of late radiation-induced injury, includ- brain regions that lead to cognitive impairment. When the entire ing radiation necrosis (Brown et al., 2005; Yuan et al., 2006). brain is irradiated, no structure will be spared that could pro- Shortly after fWBI, vascular structure and function can be altered; vide some normal or compensatory cognitive function. A recent these alterations include blood vessel dilatation, endothelial cell dose-volume histogram analysis of two prospective clinical tri- enlargement, capillary loss, and perivascular astrocyte hypertro- als by Leyrer et al. (2011) indicates that it is not the dose to phy which can lead to BBB disruption, increased permeability, the whole brain, but rather the dose to the hippocampus and and edema. This acute vascular injury has the potential to be temporal lobes that predicts the subsequent radiation-induced detectable by MRI prior to the development of radiation-induced cognitive impairment. These authors proposed a neuroanatom- demyelination and white matter necrosis (Reinhold et al., 1990; ical target theory, which suggests that selective damage to certain Li et al., 2003). brain structures may be the cause of cognitive impairment after Dynamic contrast-enhanced (DCE) MRI uses T1-weighted radiotherapy. A corollary of such a theory is that selective avoid- imaging to quantitatively assess vascular permeability by repeat- ance of these brain structures may be able to preserve cognitive edly imaging the brain prior to and following a bolus i.v. injection function. Recent advances in radiation therapy planning, includ- of a gadolinium contrast agent. By tracking the movement of the ing the advent of stereotactic localization (Shrieve et al., 1994), contrast agent through the brain as a function of post-injection trans image guidance (Gutiérrez et al., 2007), IMRT (Barani et al., 2007b; time, and calculating the transfer constant, K , using a com- Gutiérrez et al., 2007), and proton beam radiotherapy (Rosen- partment model that describes the kinetics, the passive leakage schold et al., 2011) have made it possible to selectively avoid brain of the contrast agent from the intravascular to the extravascu- structures such as the hippocampus and temporal lobes to test lar extracellular space can be obtained (Tofts et al., 1999). High trans trans this theory. K values indicate that the BBB is not intact; low K values indicate that the BBB is intact. It has been suggested that these NON-INVASIVE IMAGING BIOMARKERS OF increases in the BBB permeability after fWBI are the result of vas- RADIATION-INDUCED COGNITIVE IMPAIRMENT cular endothelial cell death (Li et al., 2003). Presently, there is no Currently, there are no validated biomarkers for determining who evidence that DCE measured changes in BBB permeability are a will/will not develop radiation-induced brain injury, including biomarker for the onset or progression of late radiation-induced cognitive impairment, or who will/will not respond favorably cognitive impairment. to therapies aimed at preventing or ameliorating these cognitive Functional MRI (fMRI) measures the oxyhemoglobin to deoxy- deficits. Radiation-induced late effects in the brain occur within hemoglobin ratio in the brain to obtain an estimate of blood the closed cranial cavity. Therefore, non-invasive techniques are flow. Oxyhemoglobin is diamagnetic and does not generate an Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 6 “fonc-02-00073” — 2012/7/18 — 14:49 — page6—#6 Greene-Schloesser et al. Radiation-induced brain injury MR signal; deoxyhemoglobin is paramagnetic and emits a rel- choline/phosphocholine (Cho/pCho), creatine/phosphocreatine atively strong MR signal. If a brain region of interest (ROI) is (Cr/pCr), glutamate (Glu), glutamine (Gln), N -acetyl-aspartate actively involved in a task, the area uses more oxygen, so the (NAA), myoinositol (mI), taurine (tau), and lactate. The concen- deoxyhemoglobin level in the ROI increases. This increase in tration of each of these metabolites can be quantified in voxels deoxyhemoglobin generates an increased MR signal, but the signal as small as ∼15 mm in the rodent brain (Shi et al., 2011) with a is out of phase with the normal brain signal, and thus, appears as a 7T MR scanner and ∼0.7 cm in humans (Robbins et al., 2012) decrease in the T2-weighted brain signal due to phase interference. with a 3T MR scanner. NAA and Glu are predominantly neuronal This decrease in the MR signal is called the blood oxygenation markers; changes in their concentrations have been associated level-dependent (BOLD) signal. with neuronal damage after fWBI (Shi et al., 2011) or neurolog- In a small study of childhood cancer survivors (n = 16), fMRI ical diseases such as Alzheimer’s (Kaiser et al., 2005; den Heijer was used to compare the activity in the visual cortex of childhood et al., 2006). Gln and mI are predominantly glial cell mark- survivors, unirradiated siblings, and unirradiated adults during a ers; changes in their concentrations have been associated with visual task (Zou et al., 2005). Overall the timing of the BOLD signal glial damage after fWBI (Pasantes-Morales et al., 2000; Shi et al., triggered by the visual event was the same across all groups. How- 2011). Cho/pCho is associated with cell membrane synthesis; ever, the BOLD signal decreased in the childhood cancer survivors concentration changes are associated with changes in cell pro- to a value less than the baseline and stayed there for a prolonged liferation and inflammatory cell infiltration (Robbins et al., 2012). time before recovering. The survivors also had an overall reduc- Cr/pCr is a marker of energy metabolism; its concentration is tion in the BOLD signal in the visual cortex when compared to relatively constant throughout the brain before and after fWBI unirradiated siblings and adults. The number of voxels that had (Sundgren and Cao, 2009). an increase in the BOLD signal was greatest for those receiving Very little preclinical data are available on MRS detection of irradiation to both the brain and spinal cord. However, there was metabolite changes in the normal brain following irradiation. no difference in the number of voxels that had an increase in Using a 4.7T MR scanner, Herynek et al. (2004) observed decreases BOLD signal between those treated with chemotherapy and those in Cr and NAA at 8 and 12 months after bilateral Gamma Knife that were not. No similar study has been undertaken with either irradiation with a dose of 35 Gy to the hippocampus of young adults or using a cognitive task. To date, we are unaware of a adult male rats; this dose resulted in severe functional and struc- BOLD study in unanesthetized pediatric or adult animal models. tural brain damage. Chan et al. (2009) used a 7T MR scanner to Consequently, there is no direct evidence at this time that fMRI is determine significant increases in Cho, Glu, tau, and lactate levels likely to identify a non-invasive biomarker of radiation-induced at 12 months after the right half of young adult male rat brains cognitive impairment. were irradiated with a single 28 Gy dose of 6 MV photons. These Arterial spin labeling (ASL) involves placing a pulsed or con- changes in white matter were confirmed histologically at post- tinuous RF field on the carotid artery in the neck to align the spins mortem. Finally, Atwood et al. (2007) used a 7T MR scanner to of the water protons in the blood (Detre et al., 2009). When the demonstrate a potential relationship between radiation-induced blood leaves the RF field, the proton spins return to their nor- changes in NAA/tCr, Glu + Gln/tCr, and mI/tCr concentra- mal state producing an MR signal. The difference between the tions in the rat brain after a 40 Gy total dose delivered in 5 Gy brain MR signal, with and without the RF field on, can be used fractions, twice per week for 4 weeks and cognitive impairment to calculate the blood flow in a specific brain region before and measured by the novel object recognition test at 12 months after after fWBI. Increases or decreases in blood flow are interpreted fWBI. However, additional experiments using this rat model of as increases or decreases in the activity or function of a specific progressive radiation-induced cognitive impairment (Figure 3) brain region. By determining the blood flow in various regions demonstrated that cognitive impairment occurred before changes associated with cognition before and after fWBI, it may be pos- in these brain metabolites (Robbins et al., 2009). Thus, none of sible to obtain a non-invasive biomarker that predicts the onset the brain metabolite changes could serve as a biomarker (i) for and/or progression of radiation-induced cognitive impairment. the onset/progression of radiation-induced cognitive impairment However, there are no reports of a correlation between blood flow or (ii) to assess the response to interventions that might pre- determined by ASL and radiation-induced cognitive impairment vent/ameliorate radiation-induced cognitive impairment in this at this time. rat model. Clinically, MRS has been used to assess metabolite changes in NON-INVASIVE PARENCHYMAL BIOMARKERS OF normal appearing white matter after fWBI (Esteve et al., 1998; RADIATION-INDUCED COGNITIVE IMPAIRMENT Walecki et al., 1999; Virta et al., 2000; Lee et al., 2004; Sund- Proton MRS is a non-invasive technique that uses an MR scanner gren et al., 2009). Acute lymphoblastic leukemia survivors, treated to (i) identify and quantify metabolites in the brain (Hoehn et al., with intrathecal methotrexate and PCI, had decreasing NAA:Cr 2001; Gillies and Morse, 2005), (ii) differentiate radiation necro- and Cho:Cr ratios as a function of time (5.6–19 years) after sis from brain tumor progression (Chong et al., 2002; Schlemmer fWBI (Chan et al., 2001). In a prospective study of 11 adult et al., 2002), and (iii) serve as a indicator of neurotoxicity fol- patients with low-grade gliomas or benign tumors such as pituitary lowing experimental (Yousem et al., 1992; Herynek et al., 2004) adenomas and meningiomas treated with fWBI, MRS detected and clinical brain irradiation (Esteve et al., 1998; Walecki et al., significant decreases in both the NAA:Cr and Cho:Cr ratios start- 1999; Virta et al., 2000; Chan et al., 2001; Lee et al., 2004; Sundgren ing 3 weeks after fWBI that persisted up to 6 months after fWBI et al., 2009). Brain metabolites that have been quantified include in normal appearing brain parenchyma (Sundgren et al., 2009). www.frontiersin.org July 2012 | Volume 2 | Article 73 | 7 “fonc-02-00073” — 2012/7/18 — 14:49 — page7—#7 Greene-Schloesser et al. Radiation-induced brain injury 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). | Relative changes in the direction of the water diffusion in FIGURE 3 Development of radiation-induced cognitive impairment as a function of time after young adult male Fischer 344 X Brown Norway 3D space after irradiation are often used to distinguish demyeli- rats were irradiated with a total 40 Gy dose of fWBI delivered as 5 Gy nation from axonal injury; this interpretation is limited to fractions, twice/week for 4 weeks. Cognition was assessed using the diffusion within white matter tracts. Differences in DTI parame- 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. ters are also found within cortical areas and represent alterations In this rat model, cognitive impairment is both progressive and not in how water diffuses through the extracellular matrix, synap- significantly different from sham-irradiated rats until ∼6 months after fWBI, tic field, and/or lightly myelinated/unmyelinated axons. DTI similar to what is observed in the clinic. ***P < 0.001. indices can be compared on a voxel-by-voxel basis throughout the brain, or by summing the voxels within each ROI and com- Similar results have been obtained in several studies with glioma paring the results between ROIs. DTI indices can also be used patients (Esteve et al., 1998; Walecki et al., 1999; Virta et al., 2000; to develop tractography maps of white matter bundles in the Lee et al., 2004). Although the rodent data suggest that identi- brain (Johansen-Berg and Behrens, 2006). However, the appli- fying an MRS biomarker for the onset/progression of cognitive cation of tractography to radiation-induced brain injury is still in impairment is unlikely, MRS may be still worthy of further study its infancy. in humans. Diffusion tensor imaging has been used to assess early white matter injury in both pediatric and adult patients treated with NON-INVASIVE DYNAMIC INTERACTION BIOMARKERS fWBI (Khong et al., 2006; Qiu et al., 2007; Nagesh et al., 2008; OF RADIATION-INDUCED COGNITIVE IMPAIRMENT Dellani et al., 2008; Haris et al., 2008). In a recent prospective Diffusion tensor imaging (DTI) assesses tissue microstructure by DTI study, patients with high-grade gliomas (n = 19), low-grade measuring the diffusion of water molecules in three-dimensional gliomas (n = 3), and benign tumors (n = 3) were imaged before, (3D) space (Le Bihan et al., 2001; Chan et al., 2009). The ability during, and after fWBI (Nagesh et al., 2008). Analyses revealed of water molecules to diffuse in brain tissue is affected predom- progressive DTI changes in the genu (anterior portion) and sple- inantly by the white matter structure (i.e., the direction and nium (posterior portion) of the corpus callosum. During the compactness of the myelinated fibers in white matter tracts) first 3 months after fWBI, dose-dependent demyelination was and the biochemical and biophysical properties of the myelin detected predominantly in regions receiving high doses. However, in these tracts. Areas with little structure allow water to freely 6 months after fWBI, this DTI detectable demyelination had spread diffuse in all directions; areas with a great amount of structure to lower dose regions, suggesting that interventions might prevent will allow water to diffuse predominantly in one direction. The this spread if initiated when demyelination was first detected at fractional anisotropy (FA) index is commonly used to indicate 3 months after fWBI (Nagesh et al., 2008). whether the water molecules in a particular region or tract are In a cross-sectional DTI study of survivors of childhood medul- free to move in all directions (spherical diffusion) or predom- loblastoma and acute lymphoblastic leukemia, FA decreases in the inantly in one direction (elliptical diffusion). FA values range frontal and parietal lobes were associated with declines in intelli- from 0 to 1; low FA values indicate spherical diffusion (little gence quotient after adjusting for the effects of age, dose, and time structure), high FA values indicate elliptical diffusion (highly after fWBI (Khong et al., 2006). The FA decreases were greater structured). DTI images are normally color-coded to indicate the in the frontal lobes than in the parietal lobes at the same radi- primary direction of the diffusion in a particular brain region ation dose (Qiu et al., 2007). In another study, FA values were (Figure 4). significantly reduced in normal appearing cerebral white matter of Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 8 “fonc-02-00073” — 2012/7/18 — 14:49 — page8—#8 Greene-Schloesser et al. Radiation-induced brain injury the temporal lobe, hippocampus, and thalamus in adult survivors either directly or indirectly, generating ROS that can modify treated with fWBI for acute lymphoblastic leukemia (Dellani et al., a cell’s molecular or functional phenotype. An acute dose- 2008). In both of these studies, age-matched unirradiated controls dependent increase in ROS has been measured in cultures of were used as the comparison group. Given that psychiatric and astrocytes, microglia, and neurons (Ramanan et al., 2008;Rob- health issues associated with a cancer diagnosis can influence cog- bins, unpublished data). In animals, stable end-products such nition, it is imperative that neurocognitive testing as well as FA as lipid peroxides and nitrotyrosine have been used to quantify measurements be obtained prior to fWBI in future studies so that the oxidative stress generated by exposure to ionizing radiation. each patient can serve as their own control. For example, irradiating one hemisphere of 8-day-old rat brains In summary, DTI is a promising non-invasive technique that is or 10-day-old mouse brains with single 4–12 Gy doses of 4 MV able to detect early changes in white matter integrity before radio- X-rays resulted in an acute time-dependent increase in nitrotyro- graphic evidence of radiation-induced demyelination or white sine in both the granular cell layer of the dentate gyrus (DG) and matter necrosis occurs (Nagesh et al., 2008). These microanatomic the subventricular zone (Fukuda et al., 2004). An acute increase changes in normal appearing white matter measure properties that in lipid peroxidation was also measured in the hippocampus of likely result from dynamic interactions between irradiated oligo- adult male mice at 2 weeks after a single 10 Gy dose of WBI dendrocytes, astrocytes, and neurons. However, to correlate these (Limoli et al., 2004). microanatomic changes to late delayed cognitive impairment will require that each patient undergo both DTI and cognitive test- OXIDATIVE STRESS ing prior to and after irradiation. Currently, there are ongoing Chronic oxidative stress is generally thought to result from an studies that obtain DTI and cognitive impairment measurements inflammatory response where irradiation activates microglia and prior to fWBI and over follow-up times as long as 18 months after causes immune cells to infiltrate the brain. These cells then gen- fWBI in an attempt to identify DTI biomarkers which predict the erate ROS which in turn activate more microglia and activate onset and progression of radiation-induced cognitive impairment more immune cells that can maintain or increase the level of (Chapman et al., 2012). oxidative stress. Interventions designed to reduce chronic oxida- Another non-invasive measure of brain function can also be tive stress provide an opportunity to prevent or ameliorate late obtained by quantifying the uptake of [18F]-2-deoxy-2-fluoro- radiation-induced brain injury, including cognitive impairment. D-glucose (FDG) during a cognitive task with PET. The FDG Oxidative stress is both difficult to measure and difficult to uptake in a brain region is an indicator of the level of neurosy- interpret, particularly in long-term studies with animals. Conse- naptic activity in that region; the neurosynaptic activity depends quently, measures of the inflammatory response to the increase on the interaction among several cell types, e.g., oligodendrocytes in oxidative stress after irradiation are usually used as a surro- (myelin integrity), astrocytes (glutamine/glutamate transport), gate. In tissue culture, irradiation of mouse microglial (BV-2) and neurons (electrical pulse generation). When non-human pri- cells significantly increased activation of AP-1, NF-κB, and the mates (NHP) were given a total fWBI dose of 40 Gy delivered cAMP response element-binding protein, CREB, within the first twice a week for 4 weeks, both low- and high-load cognitive 24 h after irradiation (Ramanan et al., 2008; Lee et al., 2010). function measured using a delayed match to sample (DMS) task Measurements of an acute inflammatory response have been decreased during the 12 months after fWBI; high-load function reported in rodent models including (i) upregulation of MCP- was impaired earlier than low-load function (Robbins et al., 2011). 1/CCL2 and MIP-2/CXCL2 mRNA levels (Kyrkanides et al., 2002; When these NHP were injected i.v. with FDG 10 min prior to Kalm et al., 2009; Lee et al., 2010), (ii) increased expression of a 40 min session on the DMS task and PET images acquired pro-inflammatory molecules such as TNFα,IL-1β, ICAM-1, and after completion of the DMS task, there was a decrease in FDG Cox-2 (Ramanan et al., 2008; Lee et al., 2010), and (iii) activation uptake in the cuneate and dorsal lateral prefrontal cortex and of pro-inflammatory transcription factors such as NFκB(Chi- an increase in FDG uptake in the thalamus and cerebellum at ang et al., 1997; Raju et al., 1999; Kyrkanides et al., 1999, 2002; 9 months after fWBI compared to the FDG uptake in these ROIs Lee et al., 2010). In a recent study, dose- and time-dependent prior to fWBI (Figure 5). Thus, the brain regions usually involved increases in transcript levels of inflammatory cytokines, activated in the DMS task did not function normally 9 months after fWBI, microglia, and activated endothelial cells were reported (Mora- and increasing the activity of brain regions not usually involved van et al., 2011). Finally, an acute infiltration of neutrophils and in the DMS task could not adequately compensate for this defi- a delayed increase in T cells, MHC II-positive cells, and CD-11c- ciency. Importantly, the DMS task and the PET technique used positive cells was observed in mice after single doses of ≥15 Gy in this NHP study can also be readily adapted for use in future (Moravan et al., 2011). clinical trials. CHRONIC INFLAMMATION PREVENTION/AMELIORATION OF RADIATION-INDUCED Measurements of a chronic inflammatory response to WBI and BRAIN INJURY fWBI in rodent models include (i) elevation of TNFα in mouse A preponderance of evidence supports the hypothesis that late brains up to 6 months post-irradiation (Hong et al., 1995), (ii) radiation-induced brain injury, including cognitive impairment, regionally-specific up-regulation of TNFα, and IL-1β; TNFα lev- is driven by acute and chronic oxidative stress and inflamma- els in cortex increased 57% more than in hippocampus, and IL-1β tory responses (Robbins and Zhao, 2004; Zhao et al., 2007a). levels in hippocampus increased 126% more than in cortex (Lee In general, ionizing radiation produces its biological effects by, et al., 2010), (iii) a marked increase in the number of activated www.frontiersin.org July 2012 | Volume 2 | Article 73 | 9 “fonc-02-00073” — 2012/7/18 — 14:49 — page9—#9 Greene-Schloesser et al. Radiation-induced brain injury FIGURE 5 | [ F]FDG-PET scans of cerebral glucose metabolism post-fWBI > Pre-fWBI: the red areas in the cerebellum and thalamus 9 months after fWBI of young adult male non-human primates. exhibited greater metabolic activity in scans obtained 9 months after fWBI Upper panel: post-fWBI < Pre-fWBI. Blue areas in the cuneate cortex than in scans obtained prior to fWBI. The color bar is the degree of intensity and prefrontal cortex exhibited less metabolic activity in scans obtained difference shown as a scale of t values with P < 0.001. Adapted from 9 months after fWBI than in scans obtained prior to fWBI. Lower panel: Robbins et al. (2012). microglia in the neurogenic zone of the DG (Monje et al., 2002), cells and astrocytes can promote/regulate neurogenesis (Palmer (iv) increased expression of the CCR2 receptor in the mouse sub- et al., 2000; Song et al., 2002). Irradiating the hippocampus results granular zone 9 months following high-LET brain irradiation in an increase in apoptosis in the subgranular zone of the DG (Rola et al., 2005), and (v) persistent microglial activation in the (Yazlovitskaya et al., 2006), a dose-dependent increased loss of NSCs (Bellinzona et al., 1996), decreased proliferation of the rodent brain (Schindler et al., 2008; Ramanan et al., 2009; Conner et al., 2010). These results provide a rationale for the use of anti- surviving NSC, and decreased NSC differentiation into neurons inflammatory-based interventions to prevent or ameliorate late (Snyder et al., 2001; Monje et al., 2002; Mizumatsu et al., 2003). radiation-induced brain injury, including cognitive impairment. Young adult rats irradiated with a single dose of 10 Gy produced only 3% of the new hippocampal neurons formed in unirradiated rats (Monje et al., 2002). In contrast to neurogenesis, gliogenesis NEUROGENESIS appears to be preserved following irradiation (Monje et al., 2003). In rodents, the hippocampus plays a major role in learning, Interestingly, all of these phenomena can be observed after doses consolidation, and retrieval of information (Eichenbaum, 2001, of ≤2 Gy that fail to produce demyelination and/or white matter 2004). Consequently, most rodent studies have focused on the necrosis. hippocampus to investigate radiation-induced brain injury. The These reductions in hippocampal neurogenesis have also been hippocampus consists of the DG, CA3, and CA1 regions; these implicated in radiation-induced cognitive impairment. A decrease regions have been implicated in both rodent and human cog- in hippocampal neurogenesis has been correlated with deficits nition. NSCs in the DG are capable of both self-renewal and in hippocampal-dependent spatial learning and memory at 3 generating neurons, astrocytes, and oligodendrocytes (Palmer months after a single 5 Gy dose of WBI to 21-day-old mice et al., 1997; Gage et al., 1998). Neurogenesis depends on the pres- (Rola et al., 2004). When young adult mice received 10 Gy of ence of a specific neurogenic microenvironment where endothelial Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 10 “fonc-02-00073” — 2012/7/18 — 14:49 — page 10 — #10 Greene-Schloesser et al. Radiation-induced brain injury focal irradiation to the hippocampus, a significant decrease in Chronic administration of the ACEI, ramipril to young adult neurogenesis and cell proliferation was detected 3 months post- male F344 rats 2 weeks after stereotactic irradiation of the rat irradiation; this reduction correlated to a decline in cognitive brain with a single dose of 30 Gy was associated with a reduc- function as assessed by the Barnes maze (Raber et al., 2004). Sim- tion in the severity of functional and histopathologic markers of ilarly, both a reduction in neurogenesis and cognitive impairment optic neuropathy assessed 6 months post-irradiation (Kim et al., have been observed in young adult rats after fWBI (Yoneoka et al., 2004). However, delaying the start of ramipril treatment to 4 1999; Shi et al., 2006; Lee et al., 2012). Thus, interventions that weeks after irradiation resulted in a failure to reduce the sever- (i) increase hippocampal neurogenesis, (ii) prevent the loss of ity of the radiation injury (Ryu et al., 2007). More recent studies NSCs, or (iii) replace lost NSCs after irradiation may prevent by Jenrow et al. (2010) have shown that ramipril produced modest or ameliorate radiation-induced brain injury, including cognitive protection against WBI-induced decreases in neurogenesis, but impairment. did not modulate radiation-induced neuroinflammation mea- sured as microglial activation. In contrast, a recent study found PRECLINICAL STUDIES OF THERAPEUTIC INTERVENTIONS that ramipril was able to ameliorate both radiation-induced cog- FOR RADIATION-INDUCED BRAIN INJURY nitive impairment (Figure 6) and microglial activation in rats after Although the exact mechanism(s) of radiation-induced brain fWBI, but had no restorative effect on neurogenesis (Lee et al., injury, including cognitive impairment is unclear, potential thera- 2012). In the Jenrow et al. (2010) study, ramipril was started 24 h peutic strategies to prevent radiation-induced brain injury include after a single dose of WBI, whereas drug was administered before, ROS scavengers, anti-inflammatory agents, and NSC transplanta- during, and after fWBI in the Lee et al. study. Thus, the timing tion. ROS scavengers have received little attention because they of the ramipril administration and/or the response after single or are likely to protect brain tumors to the same extent as they fractionated doses may explain the different results obtained in the protect normal brain. Thus, most of the preclinical investiga- two studies. At the present time, a phase I/II trial is being developed tions have focused on anti-inflammatory agents and fetal NSC to determine if ramipril can prevent/ameliorate radiation-induced transplantation. cognitive impairment in brain tumor patients. Several rodent studies designed to prevent or amelio- Chronic administration of the ARB, L-158,809, to young adult rate radiation-induced cognitive impairment have shown male rats for 3 days before, during, and for 28 or 54 weeks promise using anti-inflammatory peroxisome proliferator- after fWBI prevented the radiation-induced cognitive impairment activated (PPAR) agonists (Figure 6) that have been given to observed 26 and 52 weeks post-irradiation (Figure 6; Robbins patients for years to treat other syndromes (Derosa, 2010; McK- et al., 2009). Moreover, chronic administration of L-158,809 for 3 eage and Keating, 2011). PPARα, δ, and γ are members of the days before, during, and only 5 weeks post-irradiation prevented nuclear hormone receptor superfamily of ligand-activated tran- the cognitive impairment observed 26 weeks post-irradiation scription factors that heterodimerize with the retinoid X receptor (Robbins et al., 2009). These radiation-induced cognitive impair- to regulate gene expression (Blumberg and Evans, 1998). A grow- ments occurred without any changes in brain metabolites or gross ing body of evidence suggests that PPARs regulate inflammatory histologic changes assessed at 28 and 54 weeks post-irradiation signaling and are neuroprotective in a variety of CNS diseases (Robbins et al., 2009). Thus, both PPARγ agonists and ARBs may (Bright et al., 2008; Stahel et al., 2008; Ramanan et al., 2010). prevent/ameliorate radiation-induced cognitive impairment when Administering the PPARγ agonist, pioglitazone (Pio), to young given for only a few weeks after fWBI. adult male rats starting 3 days prior to, during, and for 4 or 54 In addition to drug therapeutics, there has been increased weeks after the completion of a total 40 Gy dose of fWBI delivered interest in the use of various stem cell therapies to restore the twice a week for 4 weeks, prevented the radiation-induced cogni- neurogenic niche and improve cognition. These studies are based tive impairment measured 52 weeks after fWBI (Figure 6; Zhao on the rationale that radiation results in a dramatic reduction et al., 2007b). However, administration of Pio for 54 weeks start- in hippocampal neurogenesis that has been linked to cognitive ing after the completion of fWBI did not significantly modulate impairment (Raber et al., 2004; Rola et al., 2004). Voluntary run- radiation-induced cognitive impairment. Based on these data, a ning has been shown to increase neurogenesis in the rodent phase I/II trial has been initiated to determine the dose of Pio that hippocampus with a concomitant improvement in spatial learn- can be given safely to brain tumor patients and obtain preliminary ing and memory after single WBI doses (Naylor et al., 2008; data on the ability of Pio to prevent/ameliorate radiation-induced Wong-Goodrich et al., 2010). Preclinical studies have also shown cognitive impairment. that pretreatment with lithium or other Akt/glycogen synthase The renin–angiotensin system (RAS) has been classically kinase-3β (GSK-3β) inhibitors are neuroprotective, preventing viewed as a complex systemic hormonal system. More recently, (i) apoptosis in the subgranular zone of the DG and (ii) the several intra-organ RAS have been identified, including a brain radiation-induced decline in hippocampal dependent memory RAS (Davisson, 2003). Thebrain RASisinvolvedinmod- in 1-week-old mice that received a single dose of 7 Gy WBI ulation of the BBB, stress, memory, and cognition (Gard, (Yazlovitskaya et al., 2006; Thotala et al., 2008). Direct injection 2002; McKinley et al., 2003). Both angiotensin-converting of NSCs into rodent brains after WBI partially restores neuroge- enzyme inhibitors (ACEI) or angiotensin type-1 receptor block- nesis and hippocampal-dependent cognitive function (Acharya ers (ARB) have proven effective in treating experimental radiation et al., 2009, 2011; Joo et al., 2012). Interestingly, these NSCs nephropathy (Moulder et al., 2003) and pneumopathy (Molteni not only differentiate into neurons, but also oligodendrocytes, et al., 2000). astrocytes, and endothelial cells that can alter the hippocampal www.frontiersin.org July 2012 | Volume 2 | Article 73 | 11 “fonc-02-00073” — 2012/7/18 — 14:49 — page 11 — #11 Greene-Schloesser et al. Radiation-induced brain injury FIGURE 6 Both RAS inhibitors and PPAR agonists prevent (B) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at radiation-induced cognitive impairment in young adult male rats that 26 weeks, (C) the PPARγ agonist, pioglitazone, before, during, and for 54 received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, weeks post-fWBI; tested at 52 weeks, and (D) the PPARα agonist, twice/week for 4 weeks, and then tested for cognition at 6–12 months fenofibrate, before, during, and for 29 weeks post-fWBI; tested at post-irradiation using the NOR task. Rats were administered, (A) the ARB, 26 weeks. *P < 0.05, **P < 0.01, ***P < 0.001 compared to sham- L-158,809 before, during, and for 54 weeks post-fWBI; tested at 52 weeks, irradiated rats. microenvironment (Joo et al., 2012). However, the use of exercise regions. These trials have been met with criticism because NSCs, or NSC transplantation to prevent/ameliorate radiation-induced like the stem cells found in other organ systems, are thought cognitive impairment in humans will require considerably more to be exquisitely sensitive to ionizing radiation; complete elim- research before it can be translated to the clinic. ination of the NSCs in rodents occurs in the range of 2–6 Gy (Barani et al., 2007a,b; Gutiérrez et al., 2007). In addition, other brain regions such as the dorsal lateral prefrontal cortex play a CLINICAL STUDIES OF THERAPEUTIC INTERVENTIONS FOR RADIATION-INDUCED BRAIN INJURY major role in human cognition, unlike in the rodent where the hippocampus dominates. Preliminary data from the University One strategy for the prevention of radiation-induced cognitive impairment in the clinic involves avoidance of brain structures of Wisconsin suggest that patients receiving doses ≥7.2 Gy to the bilateral hippocampi have worse cognitive function as mea- associated with cognitive function. Recent clinical trials have focused on avoiding the regions of adult neurogenesis, including sured by the Wechsler Memory test (Gondi et al., 2011). The the hippocampus and neural stem cell niche in the periventricular RTOG is currently conducting a single arm prospective trial using Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 12 “fonc-02-00073” — 2012/7/18 — 14:49 — page 12 — #12 Greene-Schloesser et al. Radiation-induced brain injury hippocampal-sparing IMRT. This trial intends to enroll 100 ARB are being developed. Although it is simplistic to think that patients and assess cognitive outcomes compared to historical one approach or one pharmacological intervention will eliminate controls. While technology has evolved to potentially allow for radiation-induced brain injury, including cognitive impairment hippocampal sparing, it may be premature to conduct large-scale for every patient whose brain is treated with ionizing radiation, prospective clinical trials for hippocampal sparing when brain it is highly likely that significant inroads will be made to pre- regions other than the hippocampus are involved in cognition, and vent/ameliorate this increasingly important side effect of brain the dose that eliminates neurogenesis in the human hippocampus irradiation over the next decade. is unknown. SUMMARY There are no known preventive medications for radiation- Recent improvements in systemic treatments and radiation ther- induced cognitive impairment in humans, although several pharmacologic agents have been evaluated for symptomatic man- apy techniques have resulted in over 100,000 patients in the US each year surviving long enough after fWBI to develop agement. The first category of drugs assessed were the psy- chostimulants. There are several reports (DeLong et al., 1992; radiation-induced brain injury, including cognitive impairment that significantly affects their QOL. Although modern radiation Weitzner et al., 1995; Meyers et al., 1998) using methylphenidate to treat radiation-induced fatigue and cognitive impairment. Using therapy techniques have eliminated acute and early delayed brain injury as well as most late demyelination and white matter necro- methylphenidate doses of 10-30mg twice daily in adults, fatigue sis, dynamic interactions between multiple cell types in the brain is reduced and cognitive function is enhanced. Another class of appear to be responsible for generating late radiation-induced cog- drugs are the reversible cholinesterase inhibitors such as donepezil nitive impairment that affects the QOL of most survivors. It is also (Aricept ). The Wake Forest Community Clinical Oncology Pro- likely that the radiation-induced cognitive impairment measured gram Research Base recently completed a clinical trial randomizing in long term survivors of SCLC, nasopharyngeal cancer, low- 200 brain tumor patients who survived at least 6 months after frac- tionated partial- or whole-brain irradiation to either placebo or grade glioma, non-parenchymal tumors, primary brain tumors, and metastatic brain tumors is different because their diseases are donepezil 10 mg/day for 6 months. The randomized trial was based on results of a previously completed phase II open-label study treated differently. Preclinical studies suggest that anti-inflammatory drugs may where 10 mg/day of donepezil showed significant improvement in energy level, mood, and cognitive function in an identical patient prevent/ameliorate radiation-induced cognitive impairment by intervening at various points in the inflammatory response to population or irradiated brain tumor survivors (Shaw et al., 2006). both irradiation and the presence of a brain tumor. However to In the phase II study, fatigue, mood, and cognition were also mea- date, the most effective preclinical treatments have to be given sured following a 6-week washout period from the discontinuation prior to, during, and continuously after irradiation. Given that of donepezil. Worsening in all three domains was observed. ∼50% of all brain tumor patients die in <6 months after fWBI, The RTOG has just completed a randomized placebo con- and only 50–90% of those that survive >6 months after fWBI trolled trial evaluating the efficacy of memantine, an NMDA receptor antagonist that has been shown to be effective in vascu- develop radiation-induced cognitive impairment, it is impera- tive that non-invasive biomarkers be identified that predict who lar dementia. It is hypothesized that blocking this receptor blocks ischemia-induced NMDA excitation and thus, may be neuropro- will/will not develop radiation-induced cognitive impairment, and who will/will not respond to interventions, so that treatments will tective if radiation-induced ischemia occurs after fWBI. In this study, patients were treated with either memantine or placebo be limited only to those that will ultimately benefit from them. Although the early clinical trials have had only modest success in during and for 24 weeks after fWBI. The primary endpoint of modulating radiation-induced cognitive impairment, the future the study involves memory deficits measured by the Hopkins looks promising because our knowledge of how radiation-induced Verbal Learning Test at 24 weeks. The trial has 554 patients brain injury develops, how it can be non-invasively detected, and and is now closed to accrual; to date, there are no preliminary how it can be treated has improved considerably over the past results. decade. Finally, clinical trials of other potential pharmacological media- tors of cognitive function are being developed based on preclinical ACKNOWLEDGMENTS data suggesting that anti-inflammatory agents can prevent or ame- Supported by grant numbers CA112593 (to Mike E. Robbins), liorate radiation-induced cognitive function. A phase I/II trial CA122318 (to Mike E. Robbins), and CA081861 (to Edward G. of Pio given to brain tumor patients before, during, and after Shaw). fWBI has been initiated, and phase I/II trials of ramipril and an Acharya, M. M., Christie, L. A., Lan, J. (1995). Biphasic patterns of (2007). Quantitative magnetic REFERENCES M. L., Giedzinski, E., Fike, J. R., memory deficits following moderate- resonance spectroscopy reveals Acharya, M. M., Christie, L. A., Lan, M. Rosi, S., and Limoli, C. L. (2011). dose partial-brain irradiation: neu- a potential relationship between L., Donovan, P. J., Cotman, C. W., Human neural stem cell transplan- ropsychologic outcome and pro- radiation-induced changes in rat Fike, J. R., and Limoli, C. L. (2009). tation ameliorates radiation-induced posed mechanisms. J. Clin. Oncol. 13, brain metabolites and cognitive Rescue of radiation-induced cog- cognitive dysfunction. Cancer Res. 71, 2263–2271. impairment. Radiat. Res. 168, nitive impairment through cranial 4834–4845. Atwood, T., Payne, V. 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Administration conducted in the absence of any com- duction in other forums, provided the original authors and source are credited Yousem, D. M., Lenkinski, R. E., Evans, of the peroxisomal proliferator- mercial or financial relationships that S., Allen, D., O’Brien, R., Curran, activated receptor (PPAR)γ agonist could be construed as a potential and subject to any copyright notices concerning any third-party graphics etc. W., Schnall, M., Bennett, M., Wehrli, pioglitazone during fractionated conflict of interest. Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 18 “fonc-02-00073” — 2012/7/18 — 14:49 — page 18 — #18 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Oncology Pubmed Central

Radiation-induced brain injury: A review

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Abstract

REVIEW ARTICLE published: 19 July 2012 doi: 10.3389/fonc.2012.00073 -- -- | | 1,2 1,2 1,2 1,2 Dana Greene-Schloesser , Mike E. Robbins * , Ann M. Peiffer , Edward G. Shaw , 2,3 1,2 Kenneth T. Wheeler and Michael D. Chan Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA Brain Tumor Center of Excellence, Wake Forest School of Medicine, Winston-Salem, NC, USA Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA Edited by: Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive Michael L. Freeman, Vanderbilt long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the University School of Medicine, USA human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after Reviewed by: single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although Michael L. Freeman, Vanderbilt white matter necrosis is uncommon with modern techniques, functional deficits, includ- University School of Medicine, USA Eddy S. Yang, Comprehensive Cancer ing progressive impairments in memory, attention, and executive function have become Center, University of Alabama- important, because they have profound effects on quality of life. Preclinical studies have Birmingham School of Medicine, provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. USA Given its central role in memory and neurogenesis, the majority of these studies have *Correspondence: focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to Mike E. Robbins, Department of Radiation Oncology, Wake Forest several hippocampal changes including neuroinflammation and a marked reduction in neu- School of Medicine, Medical Center rogenesis. These data have been interpreted to suggest that shielding the hippocampus Boulevard, Room 412C NRC, will prevent clinical radiation-induced cognitive impairment. However, this interpretation Mail Box #571059, Winston-Salem, may be overly simplistic. Studies using older rodents, that more closely match the adult NC 27157, USA. e-mail: mrobbins@wakehealth.edu human brain tumor population, indicate that, unlike pediatric and young adult rats, older -| Dana Greene-Schloesser and Mike E. rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Robbins have contributed equally to Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of this article. demyelination and/or white matter necrosis similar to what is observed clinically, suggest- ing 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 RADIATION-INDUCED BRAIN INJURY solely to a reduction in the proliferating capacity of glial (van den Maazen et al., 1993) or vascular endothelial (Calvo et al., Radiation-induced brain injury is often observed after fraction- ated partial or whole brain irradiation (fWBI); the syndrome 1988) cells. The loss of either of these cell types could ulti- mately produce white matter necrosis, but the loss of glial cells includes both anatomic and functional deficits. Based on the time of clinical expression (Figure 1), radiation-induced brain injury was thought to cause necrosis earlier than the loss of vascular endothelial cells. However, there is a growing awareness that is described in terms of acute, early delayed, and late delayed injury (Tofilon and Fike, 2000). Acute brain injury, expressed patients receiving fWBI can have significant cognitive impair- in days to weeks after irradiation, is rare with current radia- ment at >6 months post-irradiation even when they do not have tion therapy techniques. Early delayed brain injury occurs 1–6 detectable anatomic abnormalities (Sundgren and Cao, 2009). The months post-irradiation and can involve transient demyelina- impact of cognitive impairment on a patient’s quality of life (QOL) tion with somnolence. Although both of these early injuries can is now recognized as second only to survival in clinical trials result in severe reactions, they are normally reversible and resolve (Frost and Sloan, 2002). spontaneously. In contrast, late delayed brain injury, character- ized histopathologically by vascular abnormalities, demyelination, THE VASCULAR HYPOTHESIS OF LATE DELAYED and ultimately white matter necrosis (Schultheiss and Stephens, RADIATION-INDUCED BRAIN INJURY 1992), is usually observed >6 months post-irradiation; these late Proponents of the vascular hypothesis of late radiation-induced delayed injuries have been viewed as irreversible and progressive. brain injury argue that vascular damage leads to ischemia and sec- Classically, late radiation-induced brain injury was viewed as due ondarily to white matter necrosis. In support of this hypothesis, www.frontiersin.org July 2012 | Volume 2 | Article 73 | 1 “fonc-02-00073” — 2012/7/18 — 14:49 — page1—#1 Greene-Schloesser et al. Radiation-induced brain injury THE PARENCHYMAL HYPOTHESIS OF RADIATION-INDUCED BRAIN INJURY OLIGODENDROCYTES The parenchymal hypothesis of radiation-induced brain injury initially focused on the oligodendrocyte that is required for the formation of myelin sheaths. The key cell for generating mature oligodendrocytes is the oligodendrocyte type-2 astrocyte (O-2A) progenitor cell that loses its reproductive capacity after WBI in the rat (Raff et al., 1983). It has been hypothesized that radiation- induced loss of O-2A progenitor cells leads to a failure to replace oligodendrocytes that ultimately results in demyelination and white matter necrosis. Although the oligodendrocyte population in young adult rats has been reported to be depleted within 24 h after single WBI doses of ≥3 Gy and total fWBI doses of ≥4.5 Gy (Bellinzona et al., 1996; Shinohara et al., 1997; Kurita et al., 2001), FIGURE 1 Symptoms and timeline for the development of no change in the number of myelinated axons, the thickness of radiation-induced brain injury in patients treated with fWBI. myelin sheaths, and the cross-sectional area of myelinated axons has been measured in cognitively impaired rats 12 months after a total fWBI dose of 40 Gy delivered twice a week for 4 weeks to a large amount of data has described radiation-induced vascular middle-aged rats (Shi et al., 2009). Further, although the kinetics structural changes, including vessel wall thickening, vessel dila- of oligodendrocyte depletion is consistent with an early transient tion, and endothelial cell nuclear enlargement (Calvo et al., 1988; demyelination, it is inconsistent with the late onset of white mat- Reinhold et al., 1990; Schultheiss and Stephens, 1992). Quantita- ter necrosis (Hornsey et al., 1981). Thus, the relationship between tive studies in irradiated rat brains have also demonstrated time- radiation damage to oligodendrocytes and late radiation-induced and dose-dependent reductions in the number of endothelial cell brain injury is still unclear. nuclei, blood vessel density, and blood vessel length (Reinhold et al., 1990; Brown et al., 2007). Moreover, white matter necro- ASTROCYTES sis occurs in boron neutron capture studies where nearly all of These cells constitute approximately 50% of the total glial cell the radiation damage is to the vasculature (Morris et al., 1996). population in the brain and outnumber the neurons four to A recent study in rodents has shown that capillary rarefaction one in higher mammals (Hansson, 1988). Once viewed as play- and tissue hypoxia increased in all regions of the hippocampus ing a mere supportive role, astrocytes are now recognized as 2 months after fWBI (Warrington et al., 2011a). Paradoxically, a heterogeneous class of cells that perform diverse functions, these investigators also showed that low ambient oxygen levels including modulation of synaptic transmission and secretion of were able to restore the brain microvascular density (Warring- neurotrophic factors such as basic fibroblast growth factor to ton et al., 2011a,b) and reverse cognitive impairment (Warrington promote neurogenesis (Song et al., 2002; Seth and Koul, 2008). et al., 2012). Other studies have shown that (i) alterations of the Astrocytes have been shown to protect endothelial cells and blood–brain barrier (BBB) likely due to an imbalance in the lev- neurons from oxidative injury (Wilson, 1997). Also, juxtacrine els of the matrix metalloproteinase-2 and the metalloproteinase-2 signaling between astrocytes and endothelial cells is critical for tissue inhibitor, (ii) degradation of collagen type IV, an extracellu- generation and maintenance of a functional BBB, the vascular lar matrix component of the blood vessel basement membrane structure that restricts entry of blood-borne elements into the (Lee et al., 2012), and (iii) changes in the mRNA and protein brain (Janzer and Raff, 1987). In response to injury, astrocytes expression of VEGF, Ang-1, Tie-2, and Ang-2 (Lee et al., 2011) undergo proliferation, exhibit hypertrophic nuclei/cell bodies, occur after clinically relevant single and fWBI doses. In a recent and show increased expression of glial fibrillary acidic protein study, primary cultured mouse fetal neural stem cells injected (GFAP; Seifert et al., 2006; Yuan et al., 2006; Seth and Koul, into the tail vein after each of four 5 Gy fractions differenti- 2008; Wilson et al., 2009; Zhou et al., 2011). These reactive ated into both brain endothelial cells and a variety of brain astrocytes secrete a host of pro-inflammatory mediators such as cells; this restored the radiation-induced decrease in both cerebral cyclooxygenase (Cox)-2 and the intercellular adhesion molecule blood flow and cognitive function (Joo et al., 2012). In contrast, (ICAM)-1, which may aid the infiltration of leukocytes into the radiation-induced necrosis has been reported in the absence of brain via BBB breakdown (Kyrkanides et al., 1999; Yuan et al., vascular changes (Schultheiss and Stephens, 1992). Also the PPARγ 2006; Wilson et al., 2009; Zhou et al., 2011). Irradiating the rat agonist, pioglitazone, and the ACE inhibitor, ramipril, that prevent and mouse brain increases GFAP protein levels, both acutely radiation-induced cognitive impairment in the rat (Zhao et al., (24 h) and chronically (4–5 months; Chiang et al., 1993; Hong 2007a,b; Lee et al., 2012) do not reverse the reduction in vascular et al., 1995). Conditioned medium from irradiated microglial cells density and length that occurs after fWBI (Brown, unpublished has been shown to induce astrogliosis which might contribute to data). Consequently, late radiation-induced brain injury cannot be radiation-induced edema (Hwang et al., 2006). However, the exact solely due to vascular damage despite the large amount of evidence role of astrocytes in the overall pathogenesis of late radiation- supporting this hypothesis. induced brain injury is still unclear, but they likely contribute by Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 2 “fonc-02-00073” — 2012/7/18 — 14:49 — page2—#2 Greene-Schloesser et al. Radiation-induced brain injury interacting with both vascular and other parenchymal elements in 1993), and neuronal gene expression (Noel et al., 1998; Rosi the brain. et al., 2008). For example, irradiating the rodent brain with single and fractionated doses produces changes in (i) neuronal MICROGLIA receptor expression of the immediate-early gene activity-regulated These immune cells represent about 12% of the total brain cytoskeleton-associated protein (Arc) (Rosi et al., 2008), (ii) N - cells (Gebicke-Haerter, 2001). In an uninjured brain, microglia methyl-D-aspartic acid (NMDA) receptor subunits (Shi et al., actively monitor the microenvironment to ensure that homeostasis 2006; Machida et al., 2010), (iii) glutaminergic transmission is maintained (Stoll and Jander, 1999). Microglia express neu- (Rohde et al., 1979; Machida et al., 2010), and (iv) hippocam- rotrophins that selectively regulate (i) microglial function, (ii) pal long-term potentiation (LTP; Snyder et al., 2001; Vlkolinsky secretion of neurotrophic factors which promote neuronal sur- et al., 2008); all are important for synaptic plasticity and cognition. vival, and (iii) proliferation (Elkabes et al., 1996). After injury, Interestingly, these changes can occur in the absence of alterations microglia become activated, a process characterized by rounding in the total number of mature neurons, the number of myelinated of the cell body, retraction of cell processes, proliferation, and axons, the thickness of myelin sheaths, and/or the cross-sectional increased production of reactive oxygen species (ROS), cytokines, area of myelinated axons following fWBI (Shi et al., 2008). Thus, and chemokines that mediate neuroinflammation (Stoll and Jan- subtle cellular and/or molecular changes in the neurons themselves der, 1999; Gebicke-Haerter, 2001; Pocock and Liddle, 2001; or subtle changes in the association/communication between neu- Kim and de Vellis, 2005). rons and astrocytes must play an as yet unidentified role in late Although microglial activation plays an important role in radiation-induced cognitive impairment. phagocytosis of dead cells, sustained activation is thought to contribute to a chronic inflammatory state in the brain (Gebicke- THE DYNAMIC INTERACTIONS BETWEEN MULTIPLE CELL Haerter, 2001; Joo et al., 2012). Tissue culture studies have demon- TYPES HYPOTHESIS strated that irradiating activated microglia leads to a marked Because no single cell or tissue associated with either the vas- increase in expression of the pro-inflammatory genes TNFα,IL- cular or parenchymal hypotheses can fully explain late delayed 1β, IL-6, and Cox-2, and the chemokines, MCP-1 and ICAM-1 radiation-induced brain injury, including cognitive impairment, (Chiang et al., 1993; Kyrkanides et al., 1999, 2002; Hwang et al., radiation-induced late effects are now hypothesized to occur due 2006; Lee et al., 2010). Rodent studies have also detected (i) an to dynamic interactions between the multiple cell types in the increase in pro-inflammatory mediators within hours after irra- brain (Tofilon and Fike, 2000). Vascular endothelial cells, oligo- diating the brain (Chiang et al., 1997; Kyrkanides et al., 2002; Lee dendrocytes, astrocytes, microglia, and neurons, are now viewed et al., 2010), and (ii) an increase in the percentage of activated not as passive bystanders that merely die from radiation dam- microglia in the brain during the latent period before the expres- age, but rather as active participants in an orchestrated response sion of late radiation-induced brain injury (Mildenberger et al., to radiation injury that, theoretically, allows one to change the 1990; Chiang et al., 1997; Monje et al., 2003). Rodent studies response/outcome by intervening at numerous points in the and analysis of human brain tissue also suggest that microglial process to prevent or ameliorate the development of late radiation- activation may be associated with decreased hippocampal neuro- induced brain injury, including cognitive impairment. It is likely genesis and cognitive function (Monje et al., 2002, 2007; Raber that the successful unraveling of this puzzle will require the detec- et al., 2004). Anti-inflammatory agents such as ramipril and tion of subtle molecular, cellular, and microanatomic changes indomethacin reduce the number of activated microglia in the hip- in the brain that will clearly challenge basic science and clinical pocampus and/or perirhinal cortex and prevent radiation-induced investigators over the next decade. cognitive impairment in rodents (Monje et al., 2003; Lee et al., 2012). However, the anti-inflammatory agent, L-158, 809, has COGNITIVE IMPAIRMENT IN BRAIN TUMOR SURVIVORS no effect on microglial activation, but still prevents radiation- AFTER fWBI induced cognitive impairment (Robbins et al., 2009; Conner et al., 2010). Finally, orthotopic injections of fetal neuronal stem cells Radiation-induced cognitive impairment, including dementia, is (NSC) that form new neurons without affecting the number of reported to occur in up to 50–90% of adult brain tumor patients activated microglia reverse radiation-induced cognitive impair- who survive >6 months post-irradiation (Crossen et al., 1994; ment in rodents (Acharya et al., 2009, 2011). Thus, the exact Giovagnoli and Boiardi, 1994; Johannesen et al., 2003; Meyers and role that activated microglia play in generating radiation-induced Brown, 2006). This cognitive impairment is marked by decreased brain injury, including cognitive impairment, is still an open verbal memory, spatial memory, attention, and novel problem- question. solving ability (Hochberg and Slotnick, 1980; Twijnstra et al., 1987; Laukkanen et al., 1988; Roman and Sperduto, 1995). Nieder NEURONS et al. (1999) described significant cognitive impairment in 49% of Once considered a radioresistant population because they no patients at 2 years after treatment with fWBI; the incidence and longer could divide, neurons have now been shown to respond severity continued to rise over time (Figure 2). Chang et al. (2009) negatively to radiation. Studies have demonstrated radiation- documented a detectable cognitive impairment at 4 months after induced changes in hippocampal cellular activity (Gangloff and fWBI compared to patients treated with radiosurgery. Moreover, Haley, 1960; Bassant and Court, 1978), synaptic efficiency/spike radiation-induced cognitive impairment occasionally progresses generation (Bassant and Court, 1978; Pellmar and Lepinski, to dementia where patients experience progressive memory loss, www.frontiersin.org July 2012 | Volume 2 | Article 73 | 3 “fonc-02-00073” — 2012/7/18 — 14:49 — page3—#3 Greene-Schloesser et al. Radiation-induced brain injury assessing radiation-induced cognitive impairment (Herman et al., 2003; Kondziolka et al., 2005). The MMSE (i) does not avoid memorized learning from repeat testing, (ii) is biased against patients with lower educational backgrounds, and (iii) is rel- atively insensitive to the subtle changes in function caused by brain radiotherapy. To overcome these problems, recent cognitive assessments have focused on the specific domains that are most affected by brain irradiation (Klein et al., 2002; Shaw et al., 2006; Chang et al., 2009). Using intense neurocognitive assessments on primary and metastatic brain tumor patients has been criticized because many of their tumors recur leading to a general decline in health and death. As such, patients are generally less willing to partici- pate in intense cognitive testing as their health deteriorates, and the utility of the results from those that do participate is ques- tionable. Recently, RTOG study formulated a battery of tests | that focuses on the cognitive domains known to be affected FIGURE 2 The percentage of patients developing radiation-induced cognitive impairment as a function of time after fWBI. Adapted from by brain irradiation, including memory, verbal fluency, visual Nieder et al. (1999). motor speed, and executive function (Table 1); the estimated time of completion is ∼30 min. In recent trials, this battery of cognitive tests appears to overcome this major obstacle to ataxia, and urinary incontinence (Vigliani et al., 1999). Radiation- assessing radiation-induced cognitive impairment in brain tumor induced dementia is a rare occurrence with fraction sizes <3Gy patients. (DeAngelis et al., 1989; Klein et al., 2002). However, patients who survive >2 years after fWBI have a continually increasing risk of EVALUATION OF PATIENT POPULATIONS FOR STUDYING developing dementia over time (Scott et al., 1999). Importantly, all RADIATION-INDUCED COGNITIVE IMPAIRMENT of these late sequelae can be seen in the absence of radiographic Several patient populations have been used to study radiation- or clinical evidence of demyelination or white matter necrosis induced cognitive impairment. These populations include (Dropcho, 1991; Shaw et al., 2006). (i) patients receiving prophylactic cranial irradiation (PCI) (Twi- In spite of the relative rarity of progressing to frank dementia, jnstra et al., 1987; Laukkanen et al., 1988; Grosshans et al., 2008), radiation-induced cognitive impairment has significant effects on (ii) patients with nasopharyngeal cancer (Cheung et al., 2000; QOL. The majority of >6 month survivors of partial or whole Hsiao et al., 2010), (iii) patients with low-grade gliomas (Taphoorn brain irradiation have a symptom cluster consisting of fatigue, et al., 1994; Klein et al., 2002), (iv) patients with benign non- changes in mood, and cognitive dysfunction (Gleason et al, 2007). parenchymal brain tumors (Gondi et al., 2011), and (v) patients Results of neurocognitive testing in a phase III clinical trial (PCI with primary (Klein et al., 2002) or metastatic brain tumors P120-9801) showed a significant correlation between performance (Nieder et al., 1999). The majority of these patients have (i) pri- on the Functional Assessment of Cancer Therapy-Brain Specific mary brain tumors treated with temozolomide and a variety (FACT-Br) test and a patient’s QOL as measured by the ability of radiation therapy techniques or (ii) metastatic brain tumors to perform daily living activities (Li et al., 2008). In the Nieder treated with fWBI or radiosurgery. In general, about 50–70% et al. (1999) study, 20% of patients treated with fWBI had a >10% of these patients survive long enough (>6 months) to develop decline in Karnofsky Performance Status due to radiation-induced radiation-induced cognitive impairment that affects their QOL. cognitive impairment. Furthermore, brain tumor patients are sur- Therefore, this is the population that presents the greatest chal- viving longer due to improved radiation therapy techniques and lenge to the radiation oncologist. Nevertheless, it is also the systemic therapies (Stupp et al., 2005; Cochran et al., 2012), so population with the greatest number of confounding factors (e.g., the patient population experiencing radiation-induced cognitive short life spans with declining health, tumor effects on brain impairment is growing rapidly. Consequently, the search for (i) regions associated with cognition, prior treatment of systemic biomarkers to identify patients who will/will not develop cog- disease with a variety of chemotherapeutic agents, concurrent nitive impairment after fWBI and (ii) therapeutic strategies to treatment with chemotherapy, steroids, and neurotrophic drugs) prevent/ameliorate radiation-induced cognitive impairment have that, by themselves, can affect cognition. Therefore, studying pop- become very important. ulations, who receive fWBI but do not have fast growing tumors in the brain, could provide important data on the role that radiation ASSESSING RADIATION-INDUCED COGNITIVE damage plays in generating cognitive impairment in primary and IMPAIRMENT IN THE CLINIC metastatic brain tumor patients. The assessment of radiation-induced cognitive impairment in the SMALL CELL LUNG CANCER PATIENTS clinic has evolved over time. The mini-mental status examina- tion (MMSE), a test for global cognitive function which has been The NCI published a study on 15 SCLC patients who were validated in other cognitive disorders, is relatively insensitive for long-term survivors after PCI and found that 12 of these Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 4 “fonc-02-00073” — 2012/7/18 — 14:49 — page4—#4 Greene-Schloesser et al. Radiation-induced brain injury Table 1 | Neurocognitive batteries used in modern prospective clinical trials. Trial Intelligence Perception/psychomotor speed Memory Attention/executive function EORTC Dutch adult reading test Line bisection test Working memory task Stroop color word test Facial recognition test Visual verbal learning test Categoric word fluency test Judgment of line orientation Concept shifting test Letter-digit substitution RTOG 0614 COWA Trail-making A Hopkins verbal learning test Trail-making B RTOG 0933 N/A N/A Hopkins verbal learning test N/A One card learning test International shopping list test MDACC N/A N/A Hopkins verbal learning test N/A CCOP 97100 COWA Trail-making A California verbal learning test Trail-making B Rey Osterrieth complex figure Digit span exhibited abnormalities on neuropsychiatric testing, while seven LOW-GRADE GLIOMA PATIENTS performed below the normal range on the MMSE test (John- In a seminal publication by Klein et al. (2002), cognitive outcomes son et al., 1990). However, in a larger study of 69 SCLC of patients with low-grade glioma were compared to both patients patients who received PCI, a substantial portion of the patients with indolent lymphomas that had no CNS disease and healthy exhibited cognitive impairments prior to PCI, and multivari- controls. The radiotherapy fields used in this study generally did ate analysis could not identify any significant cognitive differ- not include the entire brain. This analysis revealed that low-grade ences before and after PCI (Grosshans et al., 2008). Finally, in gliomas, anti-epileptic medications, and radiotherapy could each another recent study, patients who received PCI had a detectable produce cognitive impairment; cognition was most affected if frac- decline in verbal memory just 6–8 weeks after completion of tions >2 Gy were used. Consequently, radiation-induced cognitive PCI (Welzel et al., 2008). Thus, the radiation-induced cogni- data from low-grade glioma patients are also not likely to provide tive impairment data from SCLC patients who receive PCI information relevant to the majority of primary and metastatic is confusing at best, probably because these patients received brain tumor patients. Shaw et al published results of a random- chemotherapy and/or larger radiation fractions that are not typ- ized trial in 200 adult low-grade glioma patients who received ical of those used to treat primary and metastatic brain tumor either 50.4 Gy or 64.8 Gy at 1.8 Gy per fraction to partial brain patients. treatment fields (Shaw et al, 2002). This is the only known modern primary brain tumor study in which patients were randomized to NASOPHARYNGEAL CANCER PATIENTS receive low- versus high dose-radiation. There were no differences Survivors of nasopharyngeal cancer offer another opportu- in survival outcomes by dose. However, the incidence of radiation nity to measure radiation-induced cognitive impairment in the necrosis (i.e., grade 3, 4 or 5 late brain toxicity) However, the 5- absence of a brain tumor. Patients treated for nasopharyn- year actuarial incidence of radiation necrosis (i.e., grade 3, 4 or 5 geal cancer routinely have high doses of radiation delivered late brain toxicity) was 10% in patients receiving 64.8 Gy versus to the bilateral temporal lobes because of the need to treat 5% for those given 50.4 Gy. the superior retropharyngeal lymph nodes. These patients have ∼70% chance of long-term survival, and thus, the poten- BENIGN NON-PARENCHYMAL BRAIN TUMOR PATIENTS tial for development of radiation-induced cognitive impair- Arguably, the ideal populations for determining the radiation ment, primarily due to damage to the temporal lobes. Che- tolerance of various brain regions are the patients with benign ung et al. (2000) reported that temporal lobe necrosis pre- non-parenchymal brain tumors such as meningiomas, pituitary dicted a worsening of cognitive impairment in 50 irradiated tumors, and schwannomas. These tumors generally do not affect nasopharyngeal cancer patients who were followed longitudi- cognition and are not treated with chemotherapy. Patients with nally with neuropsychological testing. Recently, Hsiao et al. (2010) these tumors have life expectancies long enough after fWBI to demonstrated that nasopharyngeal cancer patients treated with experience radiation-induced cognitive impairment. Finally, the intensity-modulated radiotherapy (IMRT) had a worse cogni- results of these human studies could be compared to the results tive outcome if >10% of their temporal lobe volume received of preclinical animal studies on radiation-induced brain injury, a total fractionated dose of >60 Gy than patients who received including cognitive impairment, all of which have been performed <60 Gy. in animals that have no brain tumors or neurological diseases www.frontiersin.org July 2012 | Volume 2 | Article 73 | 5 “fonc-02-00073” — 2012/7/18 — 14:49 — page5—#5 Greene-Schloesser et al. Radiation-induced brain injury (Lamproglou et al., 1995; Yoneoka et al., 1999; Raber et al., 2004; needed to study this significant side effect of brain tumor radio- Rola et al., 2004). Such a comparison could greatly facilitate the therapy. Given that radiation-induced cognitive impairment can development of molecular, cellular, or imaging biomarkers of the occur in the absence of radiographic evidence of gross anatomi- onset and progression of radiation-induced cognitive impairment cal changes, X-ray computed tomography (CT), T1/T2 magnetic or interventions that could be successfully translated to the clinic. resonance imaging (MRI), and ultrasound techniques are not Presently, the only published report on patients with benign non- likely to provide information relevant to the onset and progres- parenchymal brain tumors indicates that avoiding or lowering the sion of radiation-induced cognitive impairment. However, both dose to the hippocampus will reduce radiation-induced cognitive MRI and positron emission tomography (PET) have the ability impairment (Gondi et al., 2011); the equivalent study has not been to interrogate metabolic, physiologic, and functional properties performed in animals. of the brain. MRI utilizes magnetic fields to generate informa- From the above discussion, it is distinctly possible that tion by exciting the protons in hydrogen atoms and monitoring the molecular, cellular, and microanatomic events that lead them as they relax. Depending on the pulse sequence, differ- to radiation-induced cognitive impairment are different for ences in the magnetic susceptibility properties of tissues can be SCLC, nasopharyngeal cancer, low-grade glioma, benign non- exploited to probe various molecular, cellular, microanatomic, and parenchymal brain tumor, primary brain tumor, and metastatic physiologic properties of normal and tumor tissues. Magnetic res- brain tumor patients. Consequently, (i) identifying biomarkers of onance spectroscopy (MRS) utilizes an MR scanner to identify and the onset and progression of radiation-induced cognitive impair- quantify metabolites that reflect both the cellular properties and ment and (ii) developing therapeutic strategies to prevent or environmental conditions in specific regions of normal and tumor ameliorate radiation-induced cognitive impairment is likely to be tissues. PET utilizes radioligands that contain an atom that emits challenging for both basic scientists and physicians. a positron to interrogate the metabolic, receptor, physiologic, and functional properties of normal and tumor tissue. Theoretically, THE NEUROANATOMICAL TARGET THEORY OF these three non-invasive techniques have the ability to identify RADIATION-INDUCED COGNITIVE IMPAIRMENT biomarkers of the onset and progression of radiation-induced The target structures and dose thresholds for the development cognitive impairment. of radiation-induced cognitive impairment are of current clinical interest. Prior studies have suggested that partial brain irradia- NON-INVASIVE VASCULAR BIOMARKERS OF tion may not cause the same degree of cognitive impairment as RADIATION-INDUCED COGNITIVE IMPAIRMENT WBI (Armstrong et al., 1995; Torres et al., 2003). This observa- Vascular injury has been hypothesized to play a critical role tion could be explained by hypothesizing that there are specific in the development of late radiation-induced injury, includ- brain regions that lead to cognitive impairment. When the entire ing radiation necrosis (Brown et al., 2005; Yuan et al., 2006). brain is irradiated, no structure will be spared that could pro- Shortly after fWBI, vascular structure and function can be altered; vide some normal or compensatory cognitive function. A recent these alterations include blood vessel dilatation, endothelial cell dose-volume histogram analysis of two prospective clinical tri- enlargement, capillary loss, and perivascular astrocyte hypertro- als by Leyrer et al. (2011) indicates that it is not the dose to phy which can lead to BBB disruption, increased permeability, the whole brain, but rather the dose to the hippocampus and and edema. This acute vascular injury has the potential to be temporal lobes that predicts the subsequent radiation-induced detectable by MRI prior to the development of radiation-induced cognitive impairment. These authors proposed a neuroanatom- demyelination and white matter necrosis (Reinhold et al., 1990; ical target theory, which suggests that selective damage to certain Li et al., 2003). brain structures may be the cause of cognitive impairment after Dynamic contrast-enhanced (DCE) MRI uses T1-weighted radiotherapy. A corollary of such a theory is that selective avoid- imaging to quantitatively assess vascular permeability by repeat- ance of these brain structures may be able to preserve cognitive edly imaging the brain prior to and following a bolus i.v. injection function. Recent advances in radiation therapy planning, includ- of a gadolinium contrast agent. By tracking the movement of the ing the advent of stereotactic localization (Shrieve et al., 1994), contrast agent through the brain as a function of post-injection trans image guidance (Gutiérrez et al., 2007), IMRT (Barani et al., 2007b; time, and calculating the transfer constant, K , using a com- Gutiérrez et al., 2007), and proton beam radiotherapy (Rosen- partment model that describes the kinetics, the passive leakage schold et al., 2011) have made it possible to selectively avoid brain of the contrast agent from the intravascular to the extravascu- structures such as the hippocampus and temporal lobes to test lar extracellular space can be obtained (Tofts et al., 1999). High trans trans this theory. K values indicate that the BBB is not intact; low K values indicate that the BBB is intact. It has been suggested that these NON-INVASIVE IMAGING BIOMARKERS OF increases in the BBB permeability after fWBI are the result of vas- RADIATION-INDUCED COGNITIVE IMPAIRMENT cular endothelial cell death (Li et al., 2003). Presently, there is no Currently, there are no validated biomarkers for determining who evidence that DCE measured changes in BBB permeability are a will/will not develop radiation-induced brain injury, including biomarker for the onset or progression of late radiation-induced cognitive impairment, or who will/will not respond favorably cognitive impairment. to therapies aimed at preventing or ameliorating these cognitive Functional MRI (fMRI) measures the oxyhemoglobin to deoxy- deficits. Radiation-induced late effects in the brain occur within hemoglobin ratio in the brain to obtain an estimate of blood the closed cranial cavity. Therefore, non-invasive techniques are flow. Oxyhemoglobin is diamagnetic and does not generate an Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 6 “fonc-02-00073” — 2012/7/18 — 14:49 — page6—#6 Greene-Schloesser et al. Radiation-induced brain injury MR signal; deoxyhemoglobin is paramagnetic and emits a rel- choline/phosphocholine (Cho/pCho), creatine/phosphocreatine atively strong MR signal. If a brain region of interest (ROI) is (Cr/pCr), glutamate (Glu), glutamine (Gln), N -acetyl-aspartate actively involved in a task, the area uses more oxygen, so the (NAA), myoinositol (mI), taurine (tau), and lactate. The concen- deoxyhemoglobin level in the ROI increases. This increase in tration of each of these metabolites can be quantified in voxels deoxyhemoglobin generates an increased MR signal, but the signal as small as ∼15 mm in the rodent brain (Shi et al., 2011) with a is out of phase with the normal brain signal, and thus, appears as a 7T MR scanner and ∼0.7 cm in humans (Robbins et al., 2012) decrease in the T2-weighted brain signal due to phase interference. with a 3T MR scanner. NAA and Glu are predominantly neuronal This decrease in the MR signal is called the blood oxygenation markers; changes in their concentrations have been associated level-dependent (BOLD) signal. with neuronal damage after fWBI (Shi et al., 2011) or neurolog- In a small study of childhood cancer survivors (n = 16), fMRI ical diseases such as Alzheimer’s (Kaiser et al., 2005; den Heijer was used to compare the activity in the visual cortex of childhood et al., 2006). Gln and mI are predominantly glial cell mark- survivors, unirradiated siblings, and unirradiated adults during a ers; changes in their concentrations have been associated with visual task (Zou et al., 2005). Overall the timing of the BOLD signal glial damage after fWBI (Pasantes-Morales et al., 2000; Shi et al., triggered by the visual event was the same across all groups. How- 2011). Cho/pCho is associated with cell membrane synthesis; ever, the BOLD signal decreased in the childhood cancer survivors concentration changes are associated with changes in cell pro- to a value less than the baseline and stayed there for a prolonged liferation and inflammatory cell infiltration (Robbins et al., 2012). time before recovering. The survivors also had an overall reduc- Cr/pCr is a marker of energy metabolism; its concentration is tion in the BOLD signal in the visual cortex when compared to relatively constant throughout the brain before and after fWBI unirradiated siblings and adults. The number of voxels that had (Sundgren and Cao, 2009). an increase in the BOLD signal was greatest for those receiving Very little preclinical data are available on MRS detection of irradiation to both the brain and spinal cord. However, there was metabolite changes in the normal brain following irradiation. no difference in the number of voxels that had an increase in Using a 4.7T MR scanner, Herynek et al. (2004) observed decreases BOLD signal between those treated with chemotherapy and those in Cr and NAA at 8 and 12 months after bilateral Gamma Knife that were not. No similar study has been undertaken with either irradiation with a dose of 35 Gy to the hippocampus of young adults or using a cognitive task. To date, we are unaware of a adult male rats; this dose resulted in severe functional and struc- BOLD study in unanesthetized pediatric or adult animal models. tural brain damage. Chan et al. (2009) used a 7T MR scanner to Consequently, there is no direct evidence at this time that fMRI is determine significant increases in Cho, Glu, tau, and lactate levels likely to identify a non-invasive biomarker of radiation-induced at 12 months after the right half of young adult male rat brains cognitive impairment. were irradiated with a single 28 Gy dose of 6 MV photons. These Arterial spin labeling (ASL) involves placing a pulsed or con- changes in white matter were confirmed histologically at post- tinuous RF field on the carotid artery in the neck to align the spins mortem. Finally, Atwood et al. (2007) used a 7T MR scanner to of the water protons in the blood (Detre et al., 2009). When the demonstrate a potential relationship between radiation-induced blood leaves the RF field, the proton spins return to their nor- changes in NAA/tCr, Glu + Gln/tCr, and mI/tCr concentra- mal state producing an MR signal. The difference between the tions in the rat brain after a 40 Gy total dose delivered in 5 Gy brain MR signal, with and without the RF field on, can be used fractions, twice per week for 4 weeks and cognitive impairment to calculate the blood flow in a specific brain region before and measured by the novel object recognition test at 12 months after after fWBI. Increases or decreases in blood flow are interpreted fWBI. However, additional experiments using this rat model of as increases or decreases in the activity or function of a specific progressive radiation-induced cognitive impairment (Figure 3) brain region. By determining the blood flow in various regions demonstrated that cognitive impairment occurred before changes associated with cognition before and after fWBI, it may be pos- in these brain metabolites (Robbins et al., 2009). Thus, none of sible to obtain a non-invasive biomarker that predicts the onset the brain metabolite changes could serve as a biomarker (i) for and/or progression of radiation-induced cognitive impairment. the onset/progression of radiation-induced cognitive impairment However, there are no reports of a correlation between blood flow or (ii) to assess the response to interventions that might pre- determined by ASL and radiation-induced cognitive impairment vent/ameliorate radiation-induced cognitive impairment in this at this time. rat model. Clinically, MRS has been used to assess metabolite changes in NON-INVASIVE PARENCHYMAL BIOMARKERS OF normal appearing white matter after fWBI (Esteve et al., 1998; RADIATION-INDUCED COGNITIVE IMPAIRMENT Walecki et al., 1999; Virta et al., 2000; Lee et al., 2004; Sund- Proton MRS is a non-invasive technique that uses an MR scanner gren et al., 2009). Acute lymphoblastic leukemia survivors, treated to (i) identify and quantify metabolites in the brain (Hoehn et al., with intrathecal methotrexate and PCI, had decreasing NAA:Cr 2001; Gillies and Morse, 2005), (ii) differentiate radiation necro- and Cho:Cr ratios as a function of time (5.6–19 years) after sis from brain tumor progression (Chong et al., 2002; Schlemmer fWBI (Chan et al., 2001). In a prospective study of 11 adult et al., 2002), and (iii) serve as a indicator of neurotoxicity fol- patients with low-grade gliomas or benign tumors such as pituitary lowing experimental (Yousem et al., 1992; Herynek et al., 2004) adenomas and meningiomas treated with fWBI, MRS detected and clinical brain irradiation (Esteve et al., 1998; Walecki et al., significant decreases in both the NAA:Cr and Cho:Cr ratios start- 1999; Virta et al., 2000; Chan et al., 2001; Lee et al., 2004; Sundgren ing 3 weeks after fWBI that persisted up to 6 months after fWBI et al., 2009). Brain metabolites that have been quantified include in normal appearing brain parenchyma (Sundgren et al., 2009). www.frontiersin.org July 2012 | Volume 2 | Article 73 | 7 “fonc-02-00073” — 2012/7/18 — 14:49 — page7—#7 Greene-Schloesser et al. Radiation-induced brain injury 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). | Relative changes in the direction of the water diffusion in FIGURE 3 Development of radiation-induced cognitive impairment as a function of time after young adult male Fischer 344 X Brown Norway 3D space after irradiation are often used to distinguish demyeli- rats were irradiated with a total 40 Gy dose of fWBI delivered as 5 Gy nation from axonal injury; this interpretation is limited to fractions, twice/week for 4 weeks. Cognition was assessed using the diffusion within white matter tracts. Differences in DTI parame- 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. ters are also found within cortical areas and represent alterations In this rat model, cognitive impairment is both progressive and not in how water diffuses through the extracellular matrix, synap- significantly different from sham-irradiated rats until ∼6 months after fWBI, tic field, and/or lightly myelinated/unmyelinated axons. DTI similar to what is observed in the clinic. ***P < 0.001. indices can be compared on a voxel-by-voxel basis throughout the brain, or by summing the voxels within each ROI and com- Similar results have been obtained in several studies with glioma paring the results between ROIs. DTI indices can also be used patients (Esteve et al., 1998; Walecki et al., 1999; Virta et al., 2000; to develop tractography maps of white matter bundles in the Lee et al., 2004). Although the rodent data suggest that identi- brain (Johansen-Berg and Behrens, 2006). However, the appli- fying an MRS biomarker for the onset/progression of cognitive cation of tractography to radiation-induced brain injury is still in impairment is unlikely, MRS may be still worthy of further study its infancy. in humans. Diffusion tensor imaging has been used to assess early white matter injury in both pediatric and adult patients treated with NON-INVASIVE DYNAMIC INTERACTION BIOMARKERS fWBI (Khong et al., 2006; Qiu et al., 2007; Nagesh et al., 2008; OF RADIATION-INDUCED COGNITIVE IMPAIRMENT Dellani et al., 2008; Haris et al., 2008). In a recent prospective Diffusion tensor imaging (DTI) assesses tissue microstructure by DTI study, patients with high-grade gliomas (n = 19), low-grade measuring the diffusion of water molecules in three-dimensional gliomas (n = 3), and benign tumors (n = 3) were imaged before, (3D) space (Le Bihan et al., 2001; Chan et al., 2009). The ability during, and after fWBI (Nagesh et al., 2008). Analyses revealed of water molecules to diffuse in brain tissue is affected predom- progressive DTI changes in the genu (anterior portion) and sple- inantly by the white matter structure (i.e., the direction and nium (posterior portion) of the corpus callosum. During the compactness of the myelinated fibers in white matter tracts) first 3 months after fWBI, dose-dependent demyelination was and the biochemical and biophysical properties of the myelin detected predominantly in regions receiving high doses. However, in these tracts. Areas with little structure allow water to freely 6 months after fWBI, this DTI detectable demyelination had spread diffuse in all directions; areas with a great amount of structure to lower dose regions, suggesting that interventions might prevent will allow water to diffuse predominantly in one direction. The this spread if initiated when demyelination was first detected at fractional anisotropy (FA) index is commonly used to indicate 3 months after fWBI (Nagesh et al., 2008). whether the water molecules in a particular region or tract are In a cross-sectional DTI study of survivors of childhood medul- free to move in all directions (spherical diffusion) or predom- loblastoma and acute lymphoblastic leukemia, FA decreases in the inantly in one direction (elliptical diffusion). FA values range frontal and parietal lobes were associated with declines in intelli- from 0 to 1; low FA values indicate spherical diffusion (little gence quotient after adjusting for the effects of age, dose, and time structure), high FA values indicate elliptical diffusion (highly after fWBI (Khong et al., 2006). The FA decreases were greater structured). DTI images are normally color-coded to indicate the in the frontal lobes than in the parietal lobes at the same radi- primary direction of the diffusion in a particular brain region ation dose (Qiu et al., 2007). In another study, FA values were (Figure 4). significantly reduced in normal appearing cerebral white matter of Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 8 “fonc-02-00073” — 2012/7/18 — 14:49 — page8—#8 Greene-Schloesser et al. Radiation-induced brain injury the temporal lobe, hippocampus, and thalamus in adult survivors either directly or indirectly, generating ROS that can modify treated with fWBI for acute lymphoblastic leukemia (Dellani et al., a cell’s molecular or functional phenotype. An acute dose- 2008). In both of these studies, age-matched unirradiated controls dependent increase in ROS has been measured in cultures of were used as the comparison group. Given that psychiatric and astrocytes, microglia, and neurons (Ramanan et al., 2008;Rob- health issues associated with a cancer diagnosis can influence cog- bins, unpublished data). In animals, stable end-products such nition, it is imperative that neurocognitive testing as well as FA as lipid peroxides and nitrotyrosine have been used to quantify measurements be obtained prior to fWBI in future studies so that the oxidative stress generated by exposure to ionizing radiation. each patient can serve as their own control. For example, irradiating one hemisphere of 8-day-old rat brains In summary, DTI is a promising non-invasive technique that is or 10-day-old mouse brains with single 4–12 Gy doses of 4 MV able to detect early changes in white matter integrity before radio- X-rays resulted in an acute time-dependent increase in nitrotyro- graphic evidence of radiation-induced demyelination or white sine in both the granular cell layer of the dentate gyrus (DG) and matter necrosis occurs (Nagesh et al., 2008). These microanatomic the subventricular zone (Fukuda et al., 2004). An acute increase changes in normal appearing white matter measure properties that in lipid peroxidation was also measured in the hippocampus of likely result from dynamic interactions between irradiated oligo- adult male mice at 2 weeks after a single 10 Gy dose of WBI dendrocytes, astrocytes, and neurons. However, to correlate these (Limoli et al., 2004). microanatomic changes to late delayed cognitive impairment will require that each patient undergo both DTI and cognitive test- OXIDATIVE STRESS ing prior to and after irradiation. Currently, there are ongoing Chronic oxidative stress is generally thought to result from an studies that obtain DTI and cognitive impairment measurements inflammatory response where irradiation activates microglia and prior to fWBI and over follow-up times as long as 18 months after causes immune cells to infiltrate the brain. These cells then gen- fWBI in an attempt to identify DTI biomarkers which predict the erate ROS which in turn activate more microglia and activate onset and progression of radiation-induced cognitive impairment more immune cells that can maintain or increase the level of (Chapman et al., 2012). oxidative stress. Interventions designed to reduce chronic oxida- Another non-invasive measure of brain function can also be tive stress provide an opportunity to prevent or ameliorate late obtained by quantifying the uptake of [18F]-2-deoxy-2-fluoro- radiation-induced brain injury, including cognitive impairment. D-glucose (FDG) during a cognitive task with PET. The FDG Oxidative stress is both difficult to measure and difficult to uptake in a brain region is an indicator of the level of neurosy- interpret, particularly in long-term studies with animals. Conse- naptic activity in that region; the neurosynaptic activity depends quently, measures of the inflammatory response to the increase on the interaction among several cell types, e.g., oligodendrocytes in oxidative stress after irradiation are usually used as a surro- (myelin integrity), astrocytes (glutamine/glutamate transport), gate. In tissue culture, irradiation of mouse microglial (BV-2) and neurons (electrical pulse generation). When non-human pri- cells significantly increased activation of AP-1, NF-κB, and the mates (NHP) were given a total fWBI dose of 40 Gy delivered cAMP response element-binding protein, CREB, within the first twice a week for 4 weeks, both low- and high-load cognitive 24 h after irradiation (Ramanan et al., 2008; Lee et al., 2010). function measured using a delayed match to sample (DMS) task Measurements of an acute inflammatory response have been decreased during the 12 months after fWBI; high-load function reported in rodent models including (i) upregulation of MCP- was impaired earlier than low-load function (Robbins et al., 2011). 1/CCL2 and MIP-2/CXCL2 mRNA levels (Kyrkanides et al., 2002; When these NHP were injected i.v. with FDG 10 min prior to Kalm et al., 2009; Lee et al., 2010), (ii) increased expression of a 40 min session on the DMS task and PET images acquired pro-inflammatory molecules such as TNFα,IL-1β, ICAM-1, and after completion of the DMS task, there was a decrease in FDG Cox-2 (Ramanan et al., 2008; Lee et al., 2010), and (iii) activation uptake in the cuneate and dorsal lateral prefrontal cortex and of pro-inflammatory transcription factors such as NFκB(Chi- an increase in FDG uptake in the thalamus and cerebellum at ang et al., 1997; Raju et al., 1999; Kyrkanides et al., 1999, 2002; 9 months after fWBI compared to the FDG uptake in these ROIs Lee et al., 2010). In a recent study, dose- and time-dependent prior to fWBI (Figure 5). Thus, the brain regions usually involved increases in transcript levels of inflammatory cytokines, activated in the DMS task did not function normally 9 months after fWBI, microglia, and activated endothelial cells were reported (Mora- and increasing the activity of brain regions not usually involved van et al., 2011). Finally, an acute infiltration of neutrophils and in the DMS task could not adequately compensate for this defi- a delayed increase in T cells, MHC II-positive cells, and CD-11c- ciency. Importantly, the DMS task and the PET technique used positive cells was observed in mice after single doses of ≥15 Gy in this NHP study can also be readily adapted for use in future (Moravan et al., 2011). clinical trials. CHRONIC INFLAMMATION PREVENTION/AMELIORATION OF RADIATION-INDUCED Measurements of a chronic inflammatory response to WBI and BRAIN INJURY fWBI in rodent models include (i) elevation of TNFα in mouse A preponderance of evidence supports the hypothesis that late brains up to 6 months post-irradiation (Hong et al., 1995), (ii) radiation-induced brain injury, including cognitive impairment, regionally-specific up-regulation of TNFα, and IL-1β; TNFα lev- is driven by acute and chronic oxidative stress and inflamma- els in cortex increased 57% more than in hippocampus, and IL-1β tory responses (Robbins and Zhao, 2004; Zhao et al., 2007a). levels in hippocampus increased 126% more than in cortex (Lee In general, ionizing radiation produces its biological effects by, et al., 2010), (iii) a marked increase in the number of activated www.frontiersin.org July 2012 | Volume 2 | Article 73 | 9 “fonc-02-00073” — 2012/7/18 — 14:49 — page9—#9 Greene-Schloesser et al. Radiation-induced brain injury FIGURE 5 | [ F]FDG-PET scans of cerebral glucose metabolism post-fWBI > Pre-fWBI: the red areas in the cerebellum and thalamus 9 months after fWBI of young adult male non-human primates. exhibited greater metabolic activity in scans obtained 9 months after fWBI Upper panel: post-fWBI < Pre-fWBI. Blue areas in the cuneate cortex than in scans obtained prior to fWBI. The color bar is the degree of intensity and prefrontal cortex exhibited less metabolic activity in scans obtained difference shown as a scale of t values with P < 0.001. Adapted from 9 months after fWBI than in scans obtained prior to fWBI. Lower panel: Robbins et al. (2012). microglia in the neurogenic zone of the DG (Monje et al., 2002), cells and astrocytes can promote/regulate neurogenesis (Palmer (iv) increased expression of the CCR2 receptor in the mouse sub- et al., 2000; Song et al., 2002). Irradiating the hippocampus results granular zone 9 months following high-LET brain irradiation in an increase in apoptosis in the subgranular zone of the DG (Rola et al., 2005), and (v) persistent microglial activation in the (Yazlovitskaya et al., 2006), a dose-dependent increased loss of NSCs (Bellinzona et al., 1996), decreased proliferation of the rodent brain (Schindler et al., 2008; Ramanan et al., 2009; Conner et al., 2010). These results provide a rationale for the use of anti- surviving NSC, and decreased NSC differentiation into neurons inflammatory-based interventions to prevent or ameliorate late (Snyder et al., 2001; Monje et al., 2002; Mizumatsu et al., 2003). radiation-induced brain injury, including cognitive impairment. Young adult rats irradiated with a single dose of 10 Gy produced only 3% of the new hippocampal neurons formed in unirradiated rats (Monje et al., 2002). In contrast to neurogenesis, gliogenesis NEUROGENESIS appears to be preserved following irradiation (Monje et al., 2003). In rodents, the hippocampus plays a major role in learning, Interestingly, all of these phenomena can be observed after doses consolidation, and retrieval of information (Eichenbaum, 2001, of ≤2 Gy that fail to produce demyelination and/or white matter 2004). Consequently, most rodent studies have focused on the necrosis. hippocampus to investigate radiation-induced brain injury. The These reductions in hippocampal neurogenesis have also been hippocampus consists of the DG, CA3, and CA1 regions; these implicated in radiation-induced cognitive impairment. A decrease regions have been implicated in both rodent and human cog- in hippocampal neurogenesis has been correlated with deficits nition. NSCs in the DG are capable of both self-renewal and in hippocampal-dependent spatial learning and memory at 3 generating neurons, astrocytes, and oligodendrocytes (Palmer months after a single 5 Gy dose of WBI to 21-day-old mice et al., 1997; Gage et al., 1998). Neurogenesis depends on the pres- (Rola et al., 2004). When young adult mice received 10 Gy of ence of a specific neurogenic microenvironment where endothelial Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 10 “fonc-02-00073” — 2012/7/18 — 14:49 — page 10 — #10 Greene-Schloesser et al. Radiation-induced brain injury focal irradiation to the hippocampus, a significant decrease in Chronic administration of the ACEI, ramipril to young adult neurogenesis and cell proliferation was detected 3 months post- male F344 rats 2 weeks after stereotactic irradiation of the rat irradiation; this reduction correlated to a decline in cognitive brain with a single dose of 30 Gy was associated with a reduc- function as assessed by the Barnes maze (Raber et al., 2004). Sim- tion in the severity of functional and histopathologic markers of ilarly, both a reduction in neurogenesis and cognitive impairment optic neuropathy assessed 6 months post-irradiation (Kim et al., have been observed in young adult rats after fWBI (Yoneoka et al., 2004). However, delaying the start of ramipril treatment to 4 1999; Shi et al., 2006; Lee et al., 2012). Thus, interventions that weeks after irradiation resulted in a failure to reduce the sever- (i) increase hippocampal neurogenesis, (ii) prevent the loss of ity of the radiation injury (Ryu et al., 2007). More recent studies NSCs, or (iii) replace lost NSCs after irradiation may prevent by Jenrow et al. (2010) have shown that ramipril produced modest or ameliorate radiation-induced brain injury, including cognitive protection against WBI-induced decreases in neurogenesis, but impairment. did not modulate radiation-induced neuroinflammation mea- sured as microglial activation. In contrast, a recent study found PRECLINICAL STUDIES OF THERAPEUTIC INTERVENTIONS that ramipril was able to ameliorate both radiation-induced cog- FOR RADIATION-INDUCED BRAIN INJURY nitive impairment (Figure 6) and microglial activation in rats after Although the exact mechanism(s) of radiation-induced brain fWBI, but had no restorative effect on neurogenesis (Lee et al., injury, including cognitive impairment is unclear, potential thera- 2012). In the Jenrow et al. (2010) study, ramipril was started 24 h peutic strategies to prevent radiation-induced brain injury include after a single dose of WBI, whereas drug was administered before, ROS scavengers, anti-inflammatory agents, and NSC transplanta- during, and after fWBI in the Lee et al. study. Thus, the timing tion. ROS scavengers have received little attention because they of the ramipril administration and/or the response after single or are likely to protect brain tumors to the same extent as they fractionated doses may explain the different results obtained in the protect normal brain. Thus, most of the preclinical investiga- two studies. At the present time, a phase I/II trial is being developed tions have focused on anti-inflammatory agents and fetal NSC to determine if ramipril can prevent/ameliorate radiation-induced transplantation. cognitive impairment in brain tumor patients. Several rodent studies designed to prevent or amelio- Chronic administration of the ARB, L-158,809, to young adult rate radiation-induced cognitive impairment have shown male rats for 3 days before, during, and for 28 or 54 weeks promise using anti-inflammatory peroxisome proliferator- after fWBI prevented the radiation-induced cognitive impairment activated (PPAR) agonists (Figure 6) that have been given to observed 26 and 52 weeks post-irradiation (Figure 6; Robbins patients for years to treat other syndromes (Derosa, 2010; McK- et al., 2009). Moreover, chronic administration of L-158,809 for 3 eage and Keating, 2011). PPARα, δ, and γ are members of the days before, during, and only 5 weeks post-irradiation prevented nuclear hormone receptor superfamily of ligand-activated tran- the cognitive impairment observed 26 weeks post-irradiation scription factors that heterodimerize with the retinoid X receptor (Robbins et al., 2009). These radiation-induced cognitive impair- to regulate gene expression (Blumberg and Evans, 1998). A grow- ments occurred without any changes in brain metabolites or gross ing body of evidence suggests that PPARs regulate inflammatory histologic changes assessed at 28 and 54 weeks post-irradiation signaling and are neuroprotective in a variety of CNS diseases (Robbins et al., 2009). Thus, both PPARγ agonists and ARBs may (Bright et al., 2008; Stahel et al., 2008; Ramanan et al., 2010). prevent/ameliorate radiation-induced cognitive impairment when Administering the PPARγ agonist, pioglitazone (Pio), to young given for only a few weeks after fWBI. adult male rats starting 3 days prior to, during, and for 4 or 54 In addition to drug therapeutics, there has been increased weeks after the completion of a total 40 Gy dose of fWBI delivered interest in the use of various stem cell therapies to restore the twice a week for 4 weeks, prevented the radiation-induced cogni- neurogenic niche and improve cognition. These studies are based tive impairment measured 52 weeks after fWBI (Figure 6; Zhao on the rationale that radiation results in a dramatic reduction et al., 2007b). However, administration of Pio for 54 weeks start- in hippocampal neurogenesis that has been linked to cognitive ing after the completion of fWBI did not significantly modulate impairment (Raber et al., 2004; Rola et al., 2004). Voluntary run- radiation-induced cognitive impairment. Based on these data, a ning has been shown to increase neurogenesis in the rodent phase I/II trial has been initiated to determine the dose of Pio that hippocampus with a concomitant improvement in spatial learn- can be given safely to brain tumor patients and obtain preliminary ing and memory after single WBI doses (Naylor et al., 2008; data on the ability of Pio to prevent/ameliorate radiation-induced Wong-Goodrich et al., 2010). Preclinical studies have also shown cognitive impairment. that pretreatment with lithium or other Akt/glycogen synthase The renin–angiotensin system (RAS) has been classically kinase-3β (GSK-3β) inhibitors are neuroprotective, preventing viewed as a complex systemic hormonal system. More recently, (i) apoptosis in the subgranular zone of the DG and (ii) the several intra-organ RAS have been identified, including a brain radiation-induced decline in hippocampal dependent memory RAS (Davisson, 2003). Thebrain RASisinvolvedinmod- in 1-week-old mice that received a single dose of 7 Gy WBI ulation of the BBB, stress, memory, and cognition (Gard, (Yazlovitskaya et al., 2006; Thotala et al., 2008). Direct injection 2002; McKinley et al., 2003). Both angiotensin-converting of NSCs into rodent brains after WBI partially restores neuroge- enzyme inhibitors (ACEI) or angiotensin type-1 receptor block- nesis and hippocampal-dependent cognitive function (Acharya ers (ARB) have proven effective in treating experimental radiation et al., 2009, 2011; Joo et al., 2012). Interestingly, these NSCs nephropathy (Moulder et al., 2003) and pneumopathy (Molteni not only differentiate into neurons, but also oligodendrocytes, et al., 2000). astrocytes, and endothelial cells that can alter the hippocampal www.frontiersin.org July 2012 | Volume 2 | Article 73 | 11 “fonc-02-00073” — 2012/7/18 — 14:49 — page 11 — #11 Greene-Schloesser et al. Radiation-induced brain injury FIGURE 6 Both RAS inhibitors and PPAR agonists prevent (B) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at radiation-induced cognitive impairment in young adult male rats that 26 weeks, (C) the PPARγ agonist, pioglitazone, before, during, and for 54 received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, weeks post-fWBI; tested at 52 weeks, and (D) the PPARα agonist, twice/week for 4 weeks, and then tested for cognition at 6–12 months fenofibrate, before, during, and for 29 weeks post-fWBI; tested at post-irradiation using the NOR task. Rats were administered, (A) the ARB, 26 weeks. *P < 0.05, **P < 0.01, ***P < 0.001 compared to sham- L-158,809 before, during, and for 54 weeks post-fWBI; tested at 52 weeks, irradiated rats. microenvironment (Joo et al., 2012). However, the use of exercise regions. These trials have been met with criticism because NSCs, or NSC transplantation to prevent/ameliorate radiation-induced like the stem cells found in other organ systems, are thought cognitive impairment in humans will require considerably more to be exquisitely sensitive to ionizing radiation; complete elim- research before it can be translated to the clinic. ination of the NSCs in rodents occurs in the range of 2–6 Gy (Barani et al., 2007a,b; Gutiérrez et al., 2007). In addition, other brain regions such as the dorsal lateral prefrontal cortex play a CLINICAL STUDIES OF THERAPEUTIC INTERVENTIONS FOR RADIATION-INDUCED BRAIN INJURY major role in human cognition, unlike in the rodent where the hippocampus dominates. Preliminary data from the University One strategy for the prevention of radiation-induced cognitive impairment in the clinic involves avoidance of brain structures of Wisconsin suggest that patients receiving doses ≥7.2 Gy to the bilateral hippocampi have worse cognitive function as mea- associated with cognitive function. Recent clinical trials have focused on avoiding the regions of adult neurogenesis, including sured by the Wechsler Memory test (Gondi et al., 2011). The the hippocampus and neural stem cell niche in the periventricular RTOG is currently conducting a single arm prospective trial using Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 12 “fonc-02-00073” — 2012/7/18 — 14:49 — page 12 — #12 Greene-Schloesser et al. Radiation-induced brain injury hippocampal-sparing IMRT. This trial intends to enroll 100 ARB are being developed. Although it is simplistic to think that patients and assess cognitive outcomes compared to historical one approach or one pharmacological intervention will eliminate controls. While technology has evolved to potentially allow for radiation-induced brain injury, including cognitive impairment hippocampal sparing, it may be premature to conduct large-scale for every patient whose brain is treated with ionizing radiation, prospective clinical trials for hippocampal sparing when brain it is highly likely that significant inroads will be made to pre- regions other than the hippocampus are involved in cognition, and vent/ameliorate this increasingly important side effect of brain the dose that eliminates neurogenesis in the human hippocampus irradiation over the next decade. is unknown. SUMMARY There are no known preventive medications for radiation- Recent improvements in systemic treatments and radiation ther- induced cognitive impairment in humans, although several pharmacologic agents have been evaluated for symptomatic man- apy techniques have resulted in over 100,000 patients in the US each year surviving long enough after fWBI to develop agement. The first category of drugs assessed were the psy- chostimulants. There are several reports (DeLong et al., 1992; radiation-induced brain injury, including cognitive impairment that significantly affects their QOL. Although modern radiation Weitzner et al., 1995; Meyers et al., 1998) using methylphenidate to treat radiation-induced fatigue and cognitive impairment. Using therapy techniques have eliminated acute and early delayed brain injury as well as most late demyelination and white matter necro- methylphenidate doses of 10-30mg twice daily in adults, fatigue sis, dynamic interactions between multiple cell types in the brain is reduced and cognitive function is enhanced. Another class of appear to be responsible for generating late radiation-induced cog- drugs are the reversible cholinesterase inhibitors such as donepezil nitive impairment that affects the QOL of most survivors. It is also (Aricept ). The Wake Forest Community Clinical Oncology Pro- likely that the radiation-induced cognitive impairment measured gram Research Base recently completed a clinical trial randomizing in long term survivors of SCLC, nasopharyngeal cancer, low- 200 brain tumor patients who survived at least 6 months after frac- tionated partial- or whole-brain irradiation to either placebo or grade glioma, non-parenchymal tumors, primary brain tumors, and metastatic brain tumors is different because their diseases are donepezil 10 mg/day for 6 months. The randomized trial was based on results of a previously completed phase II open-label study treated differently. Preclinical studies suggest that anti-inflammatory drugs may where 10 mg/day of donepezil showed significant improvement in energy level, mood, and cognitive function in an identical patient prevent/ameliorate radiation-induced cognitive impairment by intervening at various points in the inflammatory response to population or irradiated brain tumor survivors (Shaw et al., 2006). both irradiation and the presence of a brain tumor. However to In the phase II study, fatigue, mood, and cognition were also mea- date, the most effective preclinical treatments have to be given sured following a 6-week washout period from the discontinuation prior to, during, and continuously after irradiation. Given that of donepezil. Worsening in all three domains was observed. ∼50% of all brain tumor patients die in <6 months after fWBI, The RTOG has just completed a randomized placebo con- and only 50–90% of those that survive >6 months after fWBI trolled trial evaluating the efficacy of memantine, an NMDA receptor antagonist that has been shown to be effective in vascu- develop radiation-induced cognitive impairment, it is impera- tive that non-invasive biomarkers be identified that predict who lar dementia. It is hypothesized that blocking this receptor blocks ischemia-induced NMDA excitation and thus, may be neuropro- will/will not develop radiation-induced cognitive impairment, and who will/will not respond to interventions, so that treatments will tective if radiation-induced ischemia occurs after fWBI. In this study, patients were treated with either memantine or placebo be limited only to those that will ultimately benefit from them. Although the early clinical trials have had only modest success in during and for 24 weeks after fWBI. The primary endpoint of modulating radiation-induced cognitive impairment, the future the study involves memory deficits measured by the Hopkins looks promising because our knowledge of how radiation-induced Verbal Learning Test at 24 weeks. The trial has 554 patients brain injury develops, how it can be non-invasively detected, and and is now closed to accrual; to date, there are no preliminary how it can be treated has improved considerably over the past results. decade. Finally, clinical trials of other potential pharmacological media- tors of cognitive function are being developed based on preclinical ACKNOWLEDGMENTS data suggesting that anti-inflammatory agents can prevent or ame- Supported by grant numbers CA112593 (to Mike E. Robbins), liorate radiation-induced cognitive function. A phase I/II trial CA122318 (to Mike E. Robbins), and CA081861 (to Edward G. of Pio given to brain tumor patients before, during, and after Shaw). fWBI has been initiated, and phase I/II trials of ramipril and an Acharya, M. M., Christie, L. A., Lan, J. (1995). Biphasic patterns of (2007). Quantitative magnetic REFERENCES M. L., Giedzinski, E., Fike, J. R., memory deficits following moderate- resonance spectroscopy reveals Acharya, M. M., Christie, L. A., Lan, M. Rosi, S., and Limoli, C. L. (2011). dose partial-brain irradiation: neu- a potential relationship between L., Donovan, P. J., Cotman, C. W., Human neural stem cell transplan- ropsychologic outcome and pro- radiation-induced changes in rat Fike, J. R., and Limoli, C. L. (2009). tation ameliorates radiation-induced posed mechanisms. J. Clin. Oncol. 13, brain metabolites and cognitive Rescue of radiation-induced cog- cognitive dysfunction. Cancer Res. 71, 2263–2271. impairment. Radiat. Res. 168, nitive impairment through cranial 4834–4845. Atwood, T., Payne, V. 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W., and Ogg, R. in Radiation Oncology, a specialty of Frontiers in Oncology. cranial irradiation. Cancer Res. 66, Oncol. Biol. Phys. 66, 860–866. J. (2005). BOLD responses to visual 11179–11186. Zhao, W., Diz, D. I., and Robbins, M. E. stimulation in survivors of childhood Copyright © 2012 Greene-Schloesser, Robbins, Peiffer, Shaw, Wheeler and Yoneoka, Y., Satoh, M., Akiyama, K., (2007a). Oxidative damage pathways cancer. Neuroimage 24, 61–69. Sano, K., Fujii, Y., and Tanaka, R. in relation to normal tissue injury. Chan. This is an open-access article dis- tributed under the terms of the Creative (1999). An experimental study of Br. J. Radiol. 80, S23–S31. radiation-induced cognitive dys- Zhao, W., Payne, V., Tommasi, E., Conflict of Interest Statement: The Commons Attribution License, which permits use, distribution and repro- function in an adult rat model. Br. J. Diz, D. I., Hsu, F.-C., and Rob- authors declare that the research was Radiol. 72, 1196–1201. bins, M. E. (2007b). Administration conducted in the absence of any com- duction in other forums, provided the original authors and source are credited Yousem, D. M., Lenkinski, R. E., Evans, of the peroxisomal proliferator- mercial or financial relationships that S., Allen, D., O’Brien, R., Curran, activated receptor (PPAR)γ agonist could be construed as a potential and subject to any copyright notices concerning any third-party graphics etc. W., Schnall, M., Bennett, M., Wehrli, pioglitazone during fractionated conflict of interest. Frontiers in Oncology | Radiation Oncology July 2012 | Volume 2 | Article 73 | 18 “fonc-02-00073” — 2012/7/18 — 14:49 — page 18 — #18

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