An initial investigation of serum cytokine levels in patients with gadolinium retention

Maecker, Holden T.; Wang, Weiqi; Rosenberg-Hasson, Yael; Semelka, Richard C.; Hickey, Joseph; Koran, Lorrin M.

doi:10.1590/0100-3984.2019.0075

Cited by 17 publications

(33 citation statements)

References 30 publications

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“…Our opinion is that the authors of that paper were reporting a case of GDD and not fibromyalgia. Another recent study showed that cytokine profiles determined from serum samples differed between individuals with GDD and those in a group of age-and gender-matched controls (21) .…”

Section: Discussionmentioning

confidence: 98%

Physicians with self-diagnosed gadolinium deposition disease: a case series

Semelka¹,

Ramalho

2021

Radiol Bras

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Objective: The objective of this study was to allow physicians with self-diagnosed gadolinium deposition disease symptoms to report their own experience. Materials and Methods: Nine physicians (seven females), with a mean age of 50.5 ± 8.3 years, participated in this case series. Nationalities were American (n = 6), British, Portuguese, and Romanian. Medical practices included internal medicine (n = 2), trauma surgery, ophthalmology, gastroenterology, psychiatry, family medicine, obstetrics/gynecology, and general practice. Results: Genetically, eight of the physicians were of central European origin. Underlying autoimmune conditions were present in four. Symptoms developed after a single injection in one physician and after multiple injections in eight. The precipitating agent was gadobenate dimeglumine in four physicians, gadobutrol in three, gadoterate meglumine in one, and gadopentetate dimeglumine in one. The most consistent symptoms were a burning sensation, brain fog, fatigue, distal paresthesia, fasciculations, headache, and insomnia. Eight of the physicians were compelled to change their practice of medicine. Conclusion: In the various physicians, gadolinium deposition disease showed common features and had a substantial impact on daily activity. Physicians are educated reporters on disease, so their personal descriptions should spark interest in further research.

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Section: Discussionmentioning

confidence: 98%

Physicians with self-diagnosed gadolinium deposition disease: a case series

Semelka¹,

Ramalho

2021

Radiol Bras

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“…Reduced levels suggest that retained Gd lowers mitochondrial resistance to adverse stressors, including possibly the increased levels of pro-inflammatory cytokines reported in GDD (Maecker et al, 2020). Again, confirmation in unextracted NDEVs and intact mitochondria is required.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Low GdCl 3 and GBCA concentrations induced cytokine release in mouse macrophages, including TNF-α, IL-6, and IL-10, increased ROS, and suppressed Ψ m [4]. As our cohort was a subset of GDD patients with higher peripheral TNF-α and IL-6 in association with new onset frequent headaches and neuropathic pain [23], the consistently elevated 5-methylthioadenosine (MTA), decreased adenosine, and altered arachidonic acid (AA) we observed may be clinically meaningful. MTA is an increasingly appreciated metabolic regulator of susceptibility and severity in sepsis; high plasma levels correlate strongly and positively with IL-6 and IL-8, and weakly with TNF-α, and signal a worse prognosis due to hyperinflammation [49].…”

Section: Discussionmentioning

confidence: 79%

“…The shortest time from symptom onset to blood draw was 70 days (mean = 330 days; median = 248 days), suggesting an ongoing and potentially progressive process in some cases. Congruent with reports that GDD symptom chronicity is independent of cumulative GBCA dose and retention [23,28], no association was detected between urinary Gd and total or MD symptom scores (r = −0.12, p = 0.67; r = −0.19, p = 0.50), nor did severity correlate with days between the symptom-related MRI and symptom assessment (total: r = −0.06, p = 0.83; MD: r = −0.01, p = 0.97). However, a moderately significant association was seen between number of lifetime MRIs and MD symptom score (r = 0.53, p = 0.04), with a near-significant trend for total symptom score (r = 0.47, p = 0.08).…”

Section: Participant Clinical Characteristicsmentioning

confidence: 81%

“…Clinical assessment. Clinical and biological data from adult participants (>18 years; n = 11 female, 4 male) were utilized under a Stanford IRB-approved consent [23]. All met provisional GDD diagnostic criteria: (1) new onset (≤30 days from GBCA-assisted MRI) of ≥3 symptoms: cognitive difficulty; pain in extremity, chest wall, skin, or joint (arthralgia); frequent headaches; skin thickening and/or hyperpigmentation; and, (2) unprovoked 24h urine Gd amount exceeding the laboratory reference limit ≥28 days post-MRI.…”

Section: Methodsmentioning

confidence: 99%

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

Denmark

Ruhoy²,

Wittmann³

et al. 2022

Toxics

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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.

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An initial investigation of serum cytokine levels in patients with gadolinium retention

Cited by 17 publications

References 30 publications

Physicians with self-diagnosed gadolinium deposition disease: a case series

Physicians with self-diagnosed gadolinium deposition disease: a case series

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

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

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