Denmark DeAunne, Ruhoy Ilene, Wittmann Bryan, Ashki Haleh, Koran Lorrin M
Department of Behavioral Neuroscience, Oregon Health & Science University, 3710 SW US Veterans Hospital Road, Mail Code R&D40, Portland, OR 97239, USA.
Mount Sinai South Nassau Chiari-EDS Center, 1420 Broadway, Hewlett, NY 11557, USA.
Toxics. 2022 Jan 26;10(2):56. doi: 10.3390/toxics10020056.
Despite the impressive safety of gadolinium (Gd)-based contrast agents (GBCAs), a small number of patients report the onset of new, severe, ongoing symptoms after even a single exposure-a syndrome termed Gadolinium Deposition Disease (GDD). Mitochondrial dysfunction and oxidative stress have been repeatedly implicated by animal and in vitro studies as mechanisms of Gd/GBCA-related toxicity, and as pathogenic in other diseases with similarities in presentation. Here, we aimed to molecularly characterize and explore potential metabolic associations with GDD symptoms. Detailed clinical phenotypes were systematically obtained for a small cohort of individuals ( = 15) with persistent symptoms attributed to a GBCA-enhanced MRI and consistent with provisional diagnostic criteria for GDD. Global untargeted mass spectroscopy-based metabolomics analyses were performed on plasma samples and examined for relevance with both single marker and pathways approaches. In addition to GDD criteria, frequently reported symptoms resembled those of patients with known mitochondrial-related diseases. Plasma differences compared to a healthy, asymptomatic reference cohort were suggested for 45 of 813 biochemicals. A notable proportion of these are associated with mitochondrial function and related disorders, including nucleotide and energy superpathways, which were over-represented. Although early evidence, coincident clinical and biochemical indications of potential mitochondrial involvement in GDD are remarkable in light of preclinical models showing adverse Gd/GBCA effects on multiple aspects of mitochondrial function. Further research on the potential contributory role of these markers and pathways in persistent symptoms attributed to GBCA exposure is recommended.
尽管钆（Gd）基造影剂（GBCAs）具有令人印象深刻的安全性，但仍有少数患者在即使仅接受一次注射后就报告出现新的、严重的、持续的症状——一种称为钆沉积病（GDD）的综合征。动物和体外研究多次表明，线粒体功能障碍和氧化应激是Gd/GBCA相关毒性的机制，并且在其他表现相似的疾病中具有致病性。在此，我们旨在对GDD症状进行分子特征分析并探索潜在的代谢关联。我们系统地获取了一小群个体（n = 15）的详细临床表型，这些个体因GBCA增强MRI出现持续症状，且符合GDD的临时诊断标准。对血浆样本进行了基于非靶向质谱的全代谢组学分析，并通过单一标志物和代谢途径方法检查其相关性。除了GDD标准外，经常报告的症状与已知线粒体相关疾病患者的症状相似。在813种生物化学物质中，有45种显示与健康无症状参考队列相比血浆存在差异。其中相当一部分与线粒体功能及相关疾病有关，包括核苷酸和能量超级途径，这些途径在其中占比过高。尽管这只是早期证据，但鉴于临床前模型显示Gd/GBCA对线粒体功能的多个方面有不良影响，潜在线粒体参与GDD的临床和生化迹象惊人地一致。建议进一步研究这些标志物和途径在归因于GBCA暴露的持续症状中的潜在作用。
