Radiation-induced cognitive impairment and altered diffusion tensor imaging in a juvenile rat model of cranial radiotherapy

Peiffer, Ann M.; Creer, Rebecca M.; Linville, Constance; Olson, John D.; Kulkarni, Praveen; Brown, Jacquelyn A.; Riddle, David R.; Robbins, Mike E.; Brunso-Bechtold, Judy E.

doi:10.3109/09553002.2014.938278

Cited by 17 publications

(12 citation statements)

References 29 publications

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“…In children and adults who survive radiation therapy for brain cancer, decreases in FA in white matter have been reported ( 30 , 31 ). In rats, other authors have variably shown a decrease in FA in the corpus callosum 1 year after large single WBI doses ( 32 ) or no change after fractionated irradiation with larger bioequivalent doses than we used ( 33 , 34 ). Further work is needed using clinically relevant doses at later time points and including other diffusion tensor imaging parameters, such as mean diffusivity, and areas other than the corpus callosum, such as the fimbria, that have been implicated in hippocampal impairment ( 35 ) before the value of MRI in imaging white matter changes can be fully evaluated.…”

Section: Discussionmentioning

confidence: 49%

Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

Brown

Jun

Cushman

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

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Purpose In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development. Methods and Materials Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3-month) and late (6-month) phases, before behavioral testing. Results Fractional anisotropy in the splenium of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI. Conclusions The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches.

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Section: Discussionmentioning

confidence: 49%

Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

Brown

Jun

Cushman

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

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“…Gy is enough to cause cognitive dysfunction [4]. There is no doubt that radiation damage caused by high doses of radiation, but accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well [21]. A recent study showed that the longer the exposure, the greater the degree of brain damage [33].…”

Section: Factors Influencing Radiation-related Cognitive Impairmentmentioning

confidence: 99%

“…Although hippocampal injury is considered as one of the important causes of cognitive dysfunction caused by RT, some studies have found that non-hippocampal injury also can cause cognitive dysfunction, which may be related to acute and chronic vascular changes [20]. Recently results suggest that the brain white matter damage may not be a direct result of radiation but the more complicated interaction between fractionation, dose per fraction and ability of the tissue type to repair based on blood vessel density [21]. Accumulating evidence suggests that the capillary density will also be sparse when the dose of ionizing radiation is enough, and this may result in different degrees of cognitive impairment [22].…”

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confidence: 99%

Research on the Mechanism of Radiation-Related Cognitive Impairment—A Review

Zuo¹,

Huang²

2019

JCT

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Radiotherapy (RT) remains a kind of front-line treatment for the control of tumor growth, especially for brain cancer. It is well known that cognitive impairment is mainly caused by cerebral RT, but the mechanisms underlying radiation-induced cognitive impairment remain unclear. There are different views on the cognitive dysfunction caused by RT in different studies. The recently research evidences about this topic are reviewed in present work. We found a few of factors including brain injury directly caused by radiation, cerebral tissue ischemia and necrosis caused by cerebrovascular injury, oxidative stress and brain injury mediated by inflammation, etc. which play a crucial role in the cognitive dysfunction caused by radiotherapy. These have all been widely recognized, and recently evidences have also shown that potential therapeutic interventions can effectively prevent cognitive impairment.

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“…Irradiation of 10 Gy/1 f on C57BL/6J mice did not change the time spent on familiar objects and novel objects 10 to 11 weeks [42] post-irradiation, while it decreased the time spent on novel objects 12 weeks post-irradiation. Acharya implemented a series of studies evaluating the effects of neural stem cells transplantation on brain injury with the use of novel location recognition test [64][65][66][67][68]. After receiving irradiation of 10 Gy/1 f, twomonth-old athymic nude rats demonstrated a decrease of exploration ratio 1 to 4 months post-irradiation and no significant change of exploration ratio 8 months post-irradiation [47][48][49].…”

Section: Morris Water Mazementioning

confidence: 99%

The Current Utilization of Cognitive Tests in the Research of Radiation-Induced Cognitive Dysfunction in Rodent Models

Li¹,

Chen²,

Zhang³

2017

Brain Disord Ther

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Recent clinical studies suggest that radiation-induced damage to the hippocampus plays a considerable role in the cognitive dysfunction of patients after cranial irradiation. In particular, deficits in learning, memory, and spatial processing observed in patients who received WBI are thought to be related to hippocampal injury [7]. The mechanisms of radiation-induced cognitive dysfunction are not yet fully understood. According to the available knowledge, radiation-induced cognitive dysfunction is hypothesized to result from dynamic interactions between multiple cell types: vascular and glial clonogens, neurogenesis, neural function and neuroinflammation [8][9][10]. Therefore, studies into the mechanisms and preventive measures of radiation-induced cognitive dysfunction are of paramount importance to decrease the side effects of WBI and increase the quality of life of patients. To achieve this goal, widely acknowledged animal models and universally utilized cognitive tests are the prerequisite and foundation. The Establishment of Rodent ModelsRodents, including mice and rats, are the most commonly utilized animal models in medical research given their genetic background, anatomical structure, operability, and relatively low cost of use [11]. Experimental data indicated that rodents showed similar anatomical AbstractWhole brain irradiation using low LET rays has remained the mainstay to treat some primary and metastatic brain tumors. Radiation-induced cognitive dysfunction is a progressive and irreversible late side effect after whole brain irradiation and inevitably decreases the quality of life of cancer survivors. To address this negative issue, many studies have been performed to explore the mechanisms of radiation-induced cognitive dysfunction and to develop efficacious preventive and treating measures. The prerequisite and foundation of implementing a persuasive and profound study to investigate radiation-induced cognitive dysfunction is the utilization of widely acknowledged animal models and universally applied cognitive tests. In this review, articles studying radiation-induced cognitive dysfunction from 2011 to 2016 were collected. The establishment of animal models and detailed utilization of cognitive tests were analyzed and summarized. This review summarized the general range of irradiation doses and time intervals utilized and the effects of these two factors on the results of cognitive tests. changes and physiopathological mechanisms to human beings after cranial irradiation [12]. In addition, the effects of radiation on rodents could be assessed over relatively short time periods-weeks to months rather than years to decades. Anatomical and functional changes of rodents after cranial irradiation are dependent on age, dose, and sex, which are compatible with the risk factors in human patients [13]. Given that these observations are representative of the effects seen in patients, the rodent model would enable the efficient study of mechanisms and treatments.

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Radiation-induced cognitive impairment and altered diffusion tensor imaging in a juvenile rat model of cranial radiotherapy

Cited by 17 publications

References 29 publications

Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

Research on the Mechanism of Radiation-Related Cognitive Impairment—A Review

The Current Utilization of Cognitive Tests in the Research of Radiation-Induced Cognitive Dysfunction in Rodent Models

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