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.

中文翻译：

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单剂量全脑放射治疗对葡萄糖代谢和髓鞘密度的延迟作用：一项纵向PET研究。

目的

放射疗法是脑肿瘤的重要治疗选择，但正常脑组织不可避免的照射会导致认知功能障碍。所涉及的机制仍未得到很好的解释，因此，需要新的工具来研究导致脑部放射症状延迟的过程。在这项研究中，正电子发射断层扫描（PET）用于探索由脑照射引起的延迟功能改变。

材料和方法

对雄性Wistar大鼠进行单剂量25-Gy的全脑X射线辐照或假辐照。为了研究放射线对脑葡萄糖代谢和髓鞘密度的延迟影响，在基线以及第64和94天进行了¹⁸ F-氟脱氧葡萄糖（¹⁸ F-FDG）PET扫描，而N - ¹¹ C-甲基-4,4'-在基线以及照射后第60天和第90天进行二氨基二苯乙烯（¹¹ C-MeDAS）PET扫描。此外，在基线以及第59天和第89天进行了开放野外测试（OFT）和新型空间识别（NSR）测试，以研究全脑照射是否引起行为改变。

结果

全脑辐射导致体重减轻并延迟了大脑的新陈代谢，在第64天，受辐照的大鼠在所有脑区的¹⁸ F-FDG摄取均显着降低，而在对照动物中则保持不变。在第94天，仅受辐照大鼠的杏仁核和皮质大脑区域仍显示¹⁸ F-FDG摄取减少。对照动物在第60天和90天的¹¹ C-MeDAS摄取显着低于基线，表明年轻时的髓磷脂密度降低大人。在受辐照的动物中，¹¹在第60天，C-MeDAS的摄取量类似地减少，但在第90天，示踪剂的摄取量有所增加，并且不再与基线有显着差异。行为测试显示对照和受辐照动物的模式相似。在两组中，OFT在第59天和第89天均显示出显着降低的活动性，而NSR并未显示出随着时间的推移空间记忆的任何显着变化。有趣的是，在辐照的大鼠中观察到NSR与¹¹ C-MeDAS摄取之间呈正相关。

结论

全脑照射会导致脑代谢不足，而白质流失并不会伴随着这种情况。受辐照的动物随时间推移表现出与对照动物相似的行为变化，因此，脑代谢不足与行为异常无关。但是，空间记忆似乎与辐照大鼠的髓磷脂密度有关。