Please check out the accompanying podcast of this blog post (discussion of this article begins at 19:18)
Level of evidence: 3A
This study tries to expand on recent observational studies that showed increased T1 shortening in the posterior fossa and basal ganglia in patients with repeated exposures to gadolinium based intravenous contrast agents (GBCA). These investigators sought to determine whether they could definitely detected gadolinium in those structures. Deceased patients who underwent autopsy and received at least one unenhanced brain MRI (control group) or at least four gadolinium based contrast enhanced brain MRI exams (contrast group) between 2000-2014 were included.
Patients younger than 18 years, neoplastic involvement of the prescribed regions of interest, clinical documentation or MR evidence of posttreatment and/or postradiation changes in the regions of interest, multiple sclerosis, metabolic disease, metal toxicity, history of previous intravenous or intra-articular gadolinium exposure (control group only), or patients lacking precontrast axial T1-weighted MR images were excluded.
A total of 23 patients (13 contrast group and 10 control group) satisfied the inclusion and exclusion criteria. Mean T1 weighted signal intensities were computed for user defined regions of interest within the dentate nucleus, pons, basal ganglia and the pulvinar nucleus of the thalamus and normalized against signal intensity of cerebral spinal fluid to account for intra or intersequence signal intensity difference, difference among MR units, and magnetic field inhomogeneity along the primary magnetic field axis. Inductively coupled plasma mass spectroscopy and transmission electron microscopy were performed in conjunction with electron probe microanalysis on the autopsy specimens. Twelve of the 13 patients in the contrast group had intracranial neoplasms and five patients received radiation therapy. However, using the periphery of the post radiation changes on MR imaging as surrogate for outer boundary of the low dose radiation field, all harvested samples from the supratentorial and infratentorial regions of radiation exposed patients were at least 2 cm or 6 cm away from this boundary respectively.
Moderate to strong dose dependent correlation were observed between T1 shortening signal intensity changes and tissue concentration of gadolinium in all four anatomic regions with the dentate nucleus containing the highest concentration and the pons the least. Mass spectroscopy demonstrated all patients exposed to repeated GBCA had elevated levels of elementary gadolinium in the four regions of interest ranging from 0.1 to 58.8 μg gadolinium per gram of tissue. Electron microscopy showed gadolinium deposits within neuronal tissues of patients in the contrast group. Gadolinium was primarily within the endothelial wall. However, densitometry performed with wider field views showed that gadolinium had crossed the blood brain barrier and has been deposited in neuronal tissue interstitium. This study demonstrates dose dependent relationship between intravenous GBCA administration and subsequent neuronal tissue deposition. It is the first study to show direct deposition of gadolinium in the neuronal tissue interstitium. This study shows that gadolinium is being deposited in nondiseased neuronal tissue.
These findings challenge our understanding of the biodistribution of gadolinium in an intact blood brain barrier. Whether the gadolinium deposited is free or chelated is unknown. The clinical significance of these findings are undetermined.