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

DeAunne Denmark, Ilene Ruhoy, Bryan Wittmann, Haleh Ashki, Lorrin M Koran, DeAunne Denmark, Ilene Ruhoy, Bryan Wittmann, Haleh Ashki, Lorrin M Koran

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.

Keywords: gadolinium; gadolinium-based contrast agents (GBCAs); metabolomics; mitochondrial disease; oxidative stress.

Conflict of interest statement

D.D. previously received limited consulting fees and served as an advisor to Metabolon on projects prior and entirely unrelated to all work presented here. The authors declare no competing financial interest or other conflicts of interest. There were no funders other than the authors.

Figures

Figure 1
Figure 1
Pie chart depicting the proportion of biochemicals belonging to each of eight major metabolic superpathways detected in (A) the total passing filtering criteria among participants and reference cohort individuals, and (B) the subset meeting altered criteria among participants compared to the reference cohort, as described in Methods.
Figure 2
Figure 2
Specific biochemicals and their respective pathways identified as potentially altered in GBCA-exposed patients. Circles indicate individual patient Z-scores with larger sizes denoting multiple patients; bars indicate median values; black—values 1 SD above or below the normalized reference cohort mean, gray—values less than 1 SD from the normalized reference cohort mean. Bolded biochemical names indicate those for which alterations were directionally consistent across patients.

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