Altered Plasma Mitochondrial Metabolites in Persistently Symptomatic Individuals after a GBCA-Assisted MRI

Abstract

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 (n = 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.

Does Gadolinium Deposition Lead to Metabolite Alteration in the Dentate Nucleus? An MRS Study in Patients with MS

“…28 Most interesting, a recent study used untargeted mass spectroscopybased metabolomic analyses to investigate the plasma metabolite alterations after Gd administration. 20 Compared with healthy controls, patients with Gd-deposition disease showed differences in 45 biochemicals, mostly related to mitochondrial function, similar to our findings in the brain. 20 We propose that the observed increased levels of Cr in case participants might indicate a disturbance in cellular energy homeostasis.…”

“…Preclinical and clinical studies have reported in vitro neurotoxic effects of Gd exposure due to impairment of mitochondrial function and mitochondrial metabolic alterations subsequent to gadolinium deposition. 19,20 We hypothesize that Cr and lactate will show alterations due to disturbed mitochondrial metabolism. We also hoped this study would contribute to the understanding of the molecular and cellular ramifications of Gd deposition.…”

Gadolinium Deposition Disease

“…Based on these works on cytokines, our present theory is that GDD is primarily an immune-mediated inflammatory disease (IMID) that has a principal effect on tissue-resident memory T cells (NT), which have been described as the principal mediating cell in Crohn disease 18,19 and asthma 17 . Other researchers have looked at other cell products elevated in GBCA exposure and GDD, and have shown elevated serum biomarkers for mitochondrial damage 5,20,21 …”

“…In recent years, GDD has achieved generalizability, which is a critical requirement for disease recognition. Three independent groups have reported in the peer-reviewed literature on GDD 1–5 . In this review, we will describe observations reflecting whether they have achieved broad acceptance as a theory (BAT) or if it is a novel theory/opinion of our team (NT).…”

“…17 Other researchers have looked at other cell products elevated in GBCA exposure and GDD, and have shown elevated serum biomarkers for mitochondrial damage. 5,20,21…”