Gadolinium-based contrast agents induce gadolinium deposits in cerebral vessel walls

Gadolinium based MRI contrast agents (GBCAs) are used to enhance the images and allow physicians interpreting the exam to distinguish blood vessels from nearby tissue. Safety claims for the GBCAs are based on the high stability of the agents and the high solubility, leading to rapid excretion in an intact state. Yet, recent studies showed gadolinium depositions following serial administrations of GBCAs in various parts of the brain, with the dentate nucleus (DN) being most affected. While there is currently no evidence that gadolinium deposition in the brain has caused any harm to patients, an intensive debate developed about the consequences of such retention. Regulatory bodies in Europe, the US and Japan have therefore called the manufacturers to study the retention and its effect on health.

The aim of the current study was to specify the gadolinium distribution in brain tissue of patients who received serial injections of GBCAs in the low-μm range and to explore any potential pathological tissue changes caused by gadolinium deposits.

The German researchers identified thirteen autopsy cases — eight receiving GBCA administrations, five serving as controls — from the archives of the Institute of Neuropathology, University Hospital Münster, Germany. For all patients, total gadolinium quantification after acidic digestion by means of inductively coupled plasma mass spectrometry (ICP-MS) was performed. Six cases were selected for the spatially resolved quantification of gadolinium within the cerebellum and the basal ganglia by means of high-resolution laser ablation (LA)-ICP-MS. Quantitative bioimaging of tissue sections for these cases by LA-ICP-MS revealed gadolinium depositions in the walls of small blood vessels of the DN in all GBCA exposed patients, while no gadolinium was found in the control group. Additionally, the detection of phosphorus and metals like copper, zinc and iron provides evidence that transmetalation reactions might have occurred.

Figure: Results for the LA-ICP-MS analysis of a cryo autopsy brain section of patient E. Microscopic images of the cerebellum (a, b). The red rectangle represents the analysed area within the cerebellum. Corresponding quantitative distribution map of gadolinium (c) and qualitative distribution maps of phosphorus (d), copper (e), zinc (f) and iron (g). LA-ICP-MS analysis was performed with a spot size of 20 μm. Relevant areas for the analysis of the DN are marked with dotted lines (b)

Apart from the analysis of the Gd retention, histopathological and immunohistochemical examinations were performed to determine tissue reactions. No significant pathological changes of the brain tissue in the vicinity of the DN with respect to micro-/astrogliosis and neuronal loss were found in any of the patients. The absence of pathological changes was observed even for a patient who died from nephrogenic systemic fibrosis, exhibiting extremely high gadolinium concentrations within the DN. Altogether the results show that gadolinium depositions in the brain are restricted to blood vessel walls, while the neuropil is spared and apparent cellular reactions are absent.

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