Delayed effects of a single-dose whole-brain radiation therapy on glucose metabolism and myelin density: a longitudinal PET study

Abstract

Purpose

Radiotherapy is an important treatment option for brain tumors, but the unavoidable irradiation of normal brain tissue can lead to delayed cognitive impairment. The mechanisms involved are still not well explained and, therefore, new tools to investigate the processes leading to the delayed symptoms of brain irradiation are warranted. In this study, positron emission tomography (PET) is used to explore delayed functional changes induced by brain irradiation.

Materials and methods

Male Wistar rats were subjected to a single 25-Gy dose of whole brain X-ray irradiation, or sham-irradiation. To investigate delayed effects of radiation on cerebral glucose metabolism and myelin density, ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET scans were performed at baseline and on day 64 and 94, whereas N-¹¹C-methyl-4,4′-diaminostilbene (¹¹C-MeDAS) PET scans were performed at baseline and on day 60 and 90 post-irradiation. In addition, the open field test (OFT) and novel spatial recognition (NSR) test were performed at baseline and on days 59 and 89 to investigate whether whole brain irradiation induces behavioral changes.

Results

Whole-brain irradiation caused loss of bodyweight and delayed cerebral hypometabolism, with ¹⁸F-FDG uptake in all brain regions being significantly decreased in irradiated rat on day 64 while it remained unchanged in control animals. Only amygdala and cortical brain regions of irradiated rats still showed reduced ¹⁸F-FDG uptake on day 94. ¹¹C-MeDAS uptake in control animals was significantly lower on days 60 and 90 than at the baseline, suggesting a reduction in myelin density in young adults. In irradiated animals, ¹¹C-MeDAS uptake was similarly reduced on day 60, but on day 90 tracer uptake was somewhat increased and not significantly different from baseline anymore. Behavioral tests showed a similar pattern in control and irradiated animals. In both groups, the OFT showed significantly reduced mobility on days 59 and 89, whereas the NSR did not reveal any significant changes in spatial memory over time. Interestingly, a positive correlation between the NSR and ¹¹C-MeDAS uptake was observed in irradiated rats.

Conclusions

Whole-brain irradiation causes delayed brain hypometabolism, which is not accompanied by white matter loss. Irradiated animals showed similar behavioral changes over time as control animals and, therefore, cerebral hypometabolism could not be linked to behavioral abnormalities. However, spatial memory seems to be associated with myelin density in irradiated rats.

Keywords:

• Whole-brain radiation therapy
• brain injury
• glucose metabolism
• demyelination
• positron emission tomography

Acknowledgements

The authors thank David Vállez García for his support in the statistical analysis, Alexandre Shoji for his support during the image acquisition and Peter van Luijk for his support regarding the study design.

Disclosure statement

The scholarship of Andrea Parente was financed by Siemens Medical Solutions Inc. The other authors declare no conflict of interest.

Additional information

Funding

This work was supported by Siemens Medical Solutions Inc.

Notes on contributors

Andrea Parente

Andrea Parente is a PhD student at the Department of Nuclear Medicine and Molecular Imaging at University Medical Center Groningen, University of Groningen, The Netherlands. His PhD project focuses on in vivo imaging of radiotherapy-induced brain injury and evaluation of behavioral changes.

Elisa Scandiuzzi Maciel

Elisa Scandiuzzi Maciel is a 5th year medical student at the Federal University of São Paulo, Escola Paulista de Medicina, in São Paulo, Brazil. She participated in the study during a research internship at the Department of Nuclear Medicine and Molecular Imaging at the University of Groningen for one year.

Rudi A. J. O. Dierckx

Rudi A. J. O. Dierckx is the Chairman of the Medical Imaging Center consisting of the department of Nuclear Medicine Molecular Imaging and the Department of Radiology at the University Medical Center Groningen in The Netherlands. He is a board certified nuclear medicine physician. His primary research interests relate to PET studies of the human brain.

Johannes A. Langendijk

Johannes A. Langendijk is the Head of the Department of Radiation Oncology of the University Medical Center Groningen in The Netherlands. His research interests are related to radiation induced normal tissue damage and complications, development of new radiation technologies and image guided radiotherapy.

Erik F. J. de Vries

Erik F. J. de Vries is a Full Professor in Translational Molecular Imaging at the department of Nuclear Medicine and Molecular Imaging of the University Medical Center Groningen, The Netherlands. His research focuses on translational PET imaging of drug targets and inflammatory processes in neuroscience and oncology.

Janine Doorduin

Janine Doorduin is an Assistant Professor at the Department of Nuclear Medicine and Molecular Imaging of the University Medical Center Groningen, The Netherlands. Her research focuses on the role of neuroinflammation in psychiatric and neurological disorders, involving both preclinical and clinical PET studies.