From the Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of FreieUniversität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Invest Radiol. 2019 Oct;54(10):617-626. doi: 10.1097/RLI.0000000000000571.
The aim of this study was to determine in vivo if brain inflammation leads to increased gadolinium (Gd) retention in brain tissue after repeated applications of Gd-based contrast agents (GBCAs).
Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice (n = 6). Experimental autoimmune encephalomyelitis and healthy control mice (n = 4) received 2.5 mmol/kg Gd-DTPA over 10 days (8 injections, cumulated dose of 20 mmol/kg), starting at day 14 post immunization when EAE mice reached the maximal clinical disability. In a group of mice, T1-weighted 2-dimensional RARE images were acquired before the first GBCA injection and 1 day after the last injection. Mice were killed either 1 day or 10 days after the last Gd application. From each single animal, a brain hemisphere was used for Gd detection using inductively coupled plasma mass spectrometry, whereas the other hemisphere was processed for histology and synchrotron x-ray fluorescence spectroscopy (SR-XRF) analysis.
Gadolinium deposition in inflamed brains was mapped by SR-XRF 1 day after the last Gd-DTPA injections, although only mild signal hyperintensity was found on unenhanced T1-weighted images. In addition, using inductively coupled plasma mass spectrometry, we detected and quantified Gd in both healthy and EAE brains up to 10 days after the last injections. However, EAE mouse brains showed higher levels of Gd (mean ± SD, 5.3 ± 1.8 μg/g; range, 4.45-8.03 μg/g) with respect to healthy controls (mean ± SD, 2.4 ± 0.6 μg/g; range, 1.8-3.2 μg/g). By means of micro-SR-XRF, we identified submicrometric Gd hotspots in all investigated samples containing up to 5893 μg Gd/g tissue. Nano-SR-XRF further indicated that Gd small hotspots had an average size of ~160 nm diameter and were located in areas of high inflammatory activity.
After repeated administrations of Gd-DTPA, ongoing inflammation may facilitate the retention of Gd in the brain tissue. Thus, neuroinflammation should be considered as a risk factor in the recommendation on use of linear GBCA-enhanced MRI.
本研究旨在通过活体动物实验，确定脑内炎症是否会导致重复应用钆基对比剂（GBCA）后，脑组织中钆（Gd）的蓄积增加。
在雌性 SJL/J 小鼠中诱导实验性自身免疫性脑脊髓炎（EAE）（n=6）。EAE 小鼠（n=4）和健康对照组小鼠从免疫后第 14 天（EAE 小鼠达到最大临床残疾时）开始，每天接受 2.5mmol/kg Gd-DTPA 共 10 天（8 次注射，累积剂量为 20mmol/kg）。在一组小鼠中，在第一次 GBCA 注射前和最后一次注射后 1 天采集二维 RARE 序列 T1 加权图像。在最后一次 Gd 应用后 1 天或 10 天处死小鼠。从每个单独的动物中，使用电感耦合等离子体质谱法检测大脑半球中的 Gd 检测，而另一半大脑用于组织学和同步加速器 X 射线荧光光谱（SR-XRF）分析。
尽管在未增强的 T1 加权图像上仅发现轻度信号高信号，但 SR-XRF 在最后一次 Gd-DTPA 注射后 1 天即可定位炎症性脑内的 Gd 沉积。此外，使用电感耦合等离子体质谱法，我们在最后一次注射后 10 天内，在健康和 EAE 大脑中均检测到并定量了 Gd。然而，EAE 小鼠大脑中的 Gd 水平更高（平均值±标准差，5.3±1.8μg/g；范围，4.45-8.03μg/g），而健康对照组的 Gd 水平（平均值±标准差，2.4±0.6μg/g；范围，1.8-3.2μg/g）。通过微 SR-XRF，我们在所有包含高达 5893μg Gd/g 组织的研究样本中发现了亚微米级 Gd 热点。纳米 SR-XRF 进一步表明，Gd 小热点的平均直径约为 160nm，位于高炎症活性区域。
重复给予 Gd-DTPA 后，持续的炎症可能会促进 Gd 在脑组织中的蓄积。因此，神经炎症应被视为推荐使用线性 GBCA 增强 MRI 的一个危险因素。
