Altered Functional Mitochondrial Protein Levels in Plasma Neuron-Derived Extracellular Vesicles of Patients With Gadolinium Deposition

Abstract

The retention of the heavy metal, gadolinium, after a Gadolinium-Based Contrast Agent-assisted MRI may lead to a symptom cluster termed Gadolinium Deposition Disease. Little is known of the disorder’s underlying pathophysiology, but a recent study reported abnormally elevated serum levels of pro-inflammatory cytokines compared to normal controls. As a calcium channel blocker in cellular plasma and mitochondrial membranes, gadolinium also interferes with mitochondrial function. We applied to sera from nine Gadolinium Deposition Disease and two Gadolinium Storage Condition patients newly developed methods allowing isolation of plasma neuron-derived extracellular vesicles that contain reproducibly quantifiable levels of mitochondrial proteins of all major classes. Patients’ levels of five mitochondrial functional proteins were statistically significantly lower and of two significantly higher than the levels in normal controls. The patterns of differences between study patients and controls for mitochondrial dynamics and mitochondrial proteins encompassing neuronal energy generation, metabolic regulation, ion fluxes, and survival differed from those seen for patients with first episode psychosis and those with Major Depressive Disorder compared to their controls. These findings suggest that mitochondrial dysfunction due to retained gadolinium may play a role in causing Gadolinium Deposition Disease. Larger samples of both GDD and GSC patients are needed to allow not only testing the repeatability of our findings, but also investigation of relationships of specific mitochondrial protein deficiencies or excesses and concurrent cytokine, genetic, or other factors to GDD’s neurological and cognitive symptoms. Studies of neuronal mitochondrial proteins as diagnostic markers or indicators of treatment effectiveness are also warranted.

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

“…For the remaining 30 metabolites, individual Z-scores fell both above and below 1 SD of the RI mean Figure 2), with 20 either high or low in the majority of patients. In contrast to those showing complete directional consistency, Z-scores were predominantly low (12), not high (8), for biochemicals in this mixed group. Altered individual Z-scores were split (~50%) in both high and low directions for the remaining 10.…”

“…Similar effects were observed in other cell types [8], even after low-dose macrocyclic agents [9], including cell death and mitochondrial toxicity in human neurons representing basal ganglia [10], the region of highest clinical deposition [11]. Recently, neuron-derived extracellular vesicles (NDEVs) from GDD patient plasma showed altered amounts of specific mitochondrial proteins vs. controls [12]. Antioxidant pretreatment prevented neuronal Gd-induced cell death and ROS-associated endoplasmic reticulum stress, and reduced both GdCl 3 and macrocyclic GBCA-associated oxidative stress and toxicity in chronic renal failure models [13].…”

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 …”

“…Mitochondrial injury is a major effect of gadolinium, 21 and likely injury occurs in other intracellular organelles. Currently, there has been little evidence of Gd entering cells to any extent to damage cells directly; hence, our theory is that biochemicals produced by the host, likely primarily cytokines, create this intracellular damage, either by entering the cells directly or by interacting with cell membrane binding sites.…”

“…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…”