JAMA Article on Gadolinium Exposure and Parkinson's: A False Sense of Safety? -Welk B, McArthur E, Marrow SA, et al. Association between Gadolinium contrast Exposure and the Risk of Parkinsonism

Dr. Welk and colleagues conducted a retrospective review of multiple linked administrative databases from Ontario, Canada to evaluate association between Gadolinium contrast agent exposure and the risk of Parkinsonism in patients who underwent contrast enhanced MRI (1). In this large population based study, the authors have concluded that the result does not support the hypothesis that gadolinium deposits in the Globus pallidus lead to neuronal damage manifesting as Parkinsonism. This conclusion might be overreaching and it may give a false sense of safety to the reader for all gadolinium contrast agents as inference appears to be based on large number of patient data (>99000 patients who received at least 1 dose of gadolinium contrast agent). There are already many commentaries and discussions articles on the web and in the medical community that cast doubt on clinical relevance of gadolinium deposits citing this paper without considering important limitations of the study (2). These limitations also mentioned by the authors, could significantly affect the study results and may not allow to reach the above mentioned conclusion. 

One major limitation is number of injections that patients received in this study. Of the total patients included in the study 81.5% received single dose of contrast agent and only 2.5% of the patients underwent 4 or more contrast enhanced MRIs. Almost all published reports have shown that signal intensity increase in Globus Pallidus and Dentate Nucleus is observed only after multiple contrast enhanced MRI (>6 or more contrast enhanced MRIs) (3,4). Furthermore, the authors did not define type of gadolinium agents or the cumulative dose of the contrast agent administered in the studied population. This is extremely important as several studies have shown that gadolinium deposition is dependent the total cumulative dose of gadolinium as well as on chemical structure of contrast agent and thermodynamic and kinetic stability of the gadolinium molecule. Macrocyclic agents are more stable than linear agents (5,6). Signal intensity increase in the brain nuclei due to gadolinium deposits is not observed with macrocyclic agents (Dotarem, Prohance, Gadovist) as they are more stable as compared to the linear agents (Omniscan, Magnevist, Optimark, Multihance) (7,8). As 81.5% of the patients included in this study only received a single dose of gadolinium contrast agent, it is quite possible that patients receiving single dose may have received exclusively macrocyclic agents or small number of patients who received multiple doses, could have received both macrocyclic and linear agents. Based on published literature, even if all of them have received linear agents, the total administered dose is not sufficient to draw any definitive conclusion that gadolinium contrast agents are not related to Parkinsonism.

1. Welk B, McArthur E, Marrow SA, et al. Association between Gadolinium contrast Exposure and the Risk of Parkinsonism. JAMA 2016;316:96-98 
2. https://www.lawsonresearch.ca/news/study-casts-doubt-clinical-significance-gadolinium-brain-deposits 
3. Kanda T, Ishii K, Kawaguchi H, et al. High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-Based Contrast Material Radiology. 2014;270:834-841 
4. Errante Y., Cirimele V, Mallio CA, et al. Progressive Increase of T1 Signal Intensity of the Dentate Nucleus on Unenhanced Magnetic Resonance Images is Associated with Cumulative Doses of Intravenously Administered Gadodiamide in Patients with Normal Renal Function, Suggesting Dechelation Invest Radiol. 2014;49:685-690. 
5. Perazella MA. Current status of gadolinium toxicity in patients with kidney disease. Clin J Am Soc Nephrol. 2009;4:461-9 
6. Frenzel T, Lengsfeld P, Schirmer H, et al. Stability of Gadolinium-Based Magnetic Resonance Imaging Contrast Agents in Human Serum at 37C. Invest Radiol 2008;43:817-828 
7. Kanda T, Osawa, M, Hiroshi O, et al. High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration. Radiology 2015: 275: 803-809 
8. Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium Retention in the Dentate Nucleus and Globus Pallidus is Dependent on the Class of Contrast Agent. Radiology 2015;275:783-791. 

Jenny-Kate Barkin