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.
Highlights
The retention of the heavy metal gadolinium (Gd) after an magnetic resonance imaging (MRI) with a Gadolinium-Based Contrast Agent may lead to a symptom cluster termed Gadolinium Deposition Disease (GDD) that includes neuropathic pain, new onset frequent headaches, muscle fatigue, and cognitive complaints (Semelka et al, 2016a)
No clear relationship was seen between the pre- or postchelation 24-h urine amounts and the time since the most recent gadolinium based contrast agent (GBCA)-assisted MRI
Our findings of abnormal function in brain-derived mitochondria of GDD patients are the first reports utilizing plasma exosome analysis. They suggest that mitochondrial dysfunction may be involved in the pathophysiology of the neuropathic pain, “brain fog,” and muscle fatigue reported by GDD patients (Semelka et al, 2016a; Maecker et al, 2020)
Summary
The retention of the heavy metal gadolinium (Gd) after an MRI with a Gadolinium-Based Contrast Agent may lead to a symptom cluster termed Gadolinium Deposition Disease (GDD) that includes neuropathic pain, new onset frequent headaches, muscle fatigue, and cognitive complaints (Semelka et al, 2016a). Little is known of the pathophysiology underlying GDD, but a recent study reported abnormally elevated serum levels of pro-inflammatory cytokines compared to normal controls (Maecker et al, 2020). A second study of GDD patients reported abnormally elevated or reduced levels of serum cytokines during the 24 h after DTPA chelation to remove Gd (Maecker et al, 2021). Gd enhancement of cytokine levels has been observed in animal models and cell cultures. In an in vitro study of cultured rat brain cortical neurons, GdCl3 inhibited mitochondrial function, including decreasing ATP synthesis, and increased cell death (Feng et al, 2010). Clinically relevant doses of GBCAs have a toxic effect on mitochondrial respiratory function and on the viability of human basal ganglia neurons (Bower et al, 2019)
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