Brian J Nieman1, A Elizabeth de Guzman2, Lisa M Gazdzinski3, Jason P Lerch4, M Mallar Chakravarty5, Jon Pipitone6, Douglas Strother7, Chris Fryer8, Eric Bouffet9, Suzanne Laughlin10, Normand Laperriere11, Lily Riggs12, Jovanka Skocic12, Donald J Mabbott13. 1. Department of Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Electronic address: brian.nieman@utoronto.ca. 2. Department of Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 3. Department of Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada. 4. Department of Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 5. Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Quebec, Canada; Departments of Psychiatry and Biomedical Engineering, McGill University, Montreal, Quebec, Canada. 6. Kimel Family Translational Imaging Genetics Research Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 7. Alberta Children's Hospital, Calgary, Alberta, Canada; Departments of Oncology and Pediatrics, University of Calgary, Calgary, Alberta, Canada. 8. Division of Oncology/Hematology/BMT British Columbia Children's Hospital and British Columbia Women's Hospital and Health Centre, Vancouver, British Columbia, Canada; Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. 9. Department of Physiology & Experimental Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada. 10. Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada. 11. Department of Radiation Oncology, Princess Margaret Hospital/University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada. 12. Department of Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada. 13. Department of Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
Abstract
PURPOSE: Pediatric patients treated with cranial radiation are at high risk of developing lasting cognitive impairments. We sought to identify anatomical changes in both gray matter (GM) and white matter (WM) in radiation-treated patients and in mice, in which the effect of radiation can be isolated from other factors, the time course of anatomical change can be established, and the effect of treatment age can be more fully characterized. Anatomical results were compared between species. METHODS AND MATERIALS: Patients were imaged with T1-weighted magnetic resonance imaging (MRI) after radiation treatment. Nineteen radiation-treated patients were divided into groups of 7 years of age and younger (7-) and 8 years and older (8+) and were compared to 41 controls. C57BL6 mice were treated with radiation (n=52) or sham treated (n=52) between postnatal days 16 and 36 and then assessed with in vivo and/or ex vivo MRI. In both cases, measurements of WM and GM volume, cortical thickness, area and volume, and hippocampal volume were compared between groups. RESULTS: WM volume was significantly decreased following treatment in 7- and 8+ treatment groups. GM volume was unchanged overall, but cortical thickness was slightly increased in the 7- group. Results in mice mostly mirrored these changes and provided a time course of change, showing early volume loss and normal growth. Hippocampal volume showed a decreasing trend with age in patients, an effect not observed in the mouse hippocampus but present in the olfactory bulb. CONCLUSIONS: Changes in mice treated with cranial radiation are similar to those in humans, including significant WM and GM alterations. Because mice did not receive any other treatment, the similarity across species supports the expectation that radiation is causative and suggests mice provide a representative model for studying impaired brain development after cranial radiation and testing novel treatments.
PURPOSE: Pediatric patients treated with cranial radiation are at high risk of developing lasting cognitive impairments. We sought to identify anatomical changes in both gray matter (GM) and white matter (WM) in radiation-treated patients and in mice, in which the effect of radiation can be isolated from other factors, the time course of anatomical change can be established, and the effect of treatment age can be more fully characterized. Anatomical results were compared between species. METHODS AND MATERIALS: Patients were imaged with T1-weighted magnetic resonance imaging (MRI) after radiation treatment. Nineteen radiation-treated patients were divided into groups of 7 years of age and younger (7-) and 8 years and older (8+) and were compared to 41 controls. C57BL6 mice were treated with radiation (n=52) or sham treated (n=52) between postnatal days 16 and 36 and then assessed with in vivo and/or ex vivo MRI. In both cases, measurements of WM and GM volume, cortical thickness, area and volume, and hippocampal volume were compared between groups. RESULTS: WM volume was significantly decreased following treatment in 7- and 8+ treatment groups. GM volume was unchanged overall, but cortical thickness was slightly increased in the 7- group. Results in mice mostly mirrored these changes and provided a time course of change, showing early volume loss and normal growth. Hippocampal volume showed a decreasing trend with age in patients, an effect not observed in the mouse hippocampus but present in the olfactory bulb. CONCLUSIONS: Changes in mice treated with cranial radiation are similar to those in humans, including significant WM and GM alterations. Because mice did not receive any other treatment, the similarity across species supports the expectation that radiation is causative and suggests mice provide a representative model for studying impaired brain development after cranial radiation and testing novel treatments.
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