Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review

Abstract

The unexpected appearance of T1 hyperintensities, mostly in the dentate nucleus and the globus pallidus, during nonenhanced MRI was reported in 2014. This effect is associated with prior repeated administrations of gadolinium (Gd)‐based contrast agents (GBCAs) in patients with a functional blood–brain barrier (BBB). It is widely assumed that GBCAs do not cross the intact BBB, but the observation of these hypersignals raises questions regarding this assumption. This review critically discusses the mechanisms of Gd accumulation in the brain with regard to access pathways, Gd species, tissue distribution, and subcellular location. We propose the hypothesis that there is early access of Gd species to cerebrospinal fluid, followed by passive diffusion into the brain parenchyma close to the cerebral ventricles. When accessing areas rich in endogenous metals or phosphorus, the less kinetically stable GBCAs would dissociate, and Gd would bind to endogenous macromolecules, and/or precipitate within the brain tissue. It is also proposed that Gd species enter the brain parenchyma along penetrating cortical arteries in periarterial pial‐glial basement membranes and leave the brain along intramural peri‐arterial drainage (IPAD) pathways. Lastly, Gd/GBCAs may access the brain parenchyma directly from the blood through the BBB in the walls of capillaries. It is crucial to distinguish between the physiological distribution and drainage pathways for GBCAs and the possible dissociation of less thermodynamically/kinetically stable GBCAs that lead to long‐term Gd deposition in the brain. Level of Evidence 5. Technical Efficacy Stage 3.

Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure

“…Blood-CSF barrier entry may occur with soluble GBCAs present in the CSF being transported through the ependymal lining and into the brain interstitium. However the majority of CSF may drain to lymph nodes and as the extracellular matrix is anionic it may impair the negatively charged GBCAs from utilizing this pathway 37 . Gadolinium foci are found in basement membranes around capillaries suggesting entry from the blood through or around the endothelia and across the BBB 3 , 24 .…”

“…Gadolinium foci are found in basement membranes around capillaries suggesting entry from the blood through or around the endothelia and across the BBB 3 , 24 . The perivascular system (pial-glial) may be involved in GBCA entry into the brain as there is evidence that molecules may be transported across the pial-glial basement membrane and are cleared through the intramural peri-arterial drainage (IPAD) located in the smooth muscle cell basement membrane, and represents a very rapid drainage pathway 37 – 39 . Whilst short-term clearance of gadolinium from the brain is thought to involve drainage along the basement membrane of cerebral capillaries and arterioles using the IPAD pathway, the long-term clearance mechanisms are unelucidated and require further studies to better understand long-term clearance pathways 37 , 40 .…”

“…The perivascular system (pial-glial) may be involved in GBCA entry into the brain as there is evidence that molecules may be transported across the pial-glial basement membrane and are cleared through the intramural peri-arterial drainage (IPAD) located in the smooth muscle cell basement membrane, and represents a very rapid drainage pathway 37 – 39 . Whilst short-term clearance of gadolinium from the brain is thought to involve drainage along the basement membrane of cerebral capillaries and arterioles using the IPAD pathway, the long-term clearance mechanisms are unelucidated and require further studies to better understand long-term clearance pathways 37 , 40 . Using LA-ICP-MS studies to map mesoscale localization of gadolinium in the brain we see that the relative distribution of gadolinium in the brain was relatively unchanged between 1 and 50 weeks.…”

Gadolinium-based contrast agents: What we learned from acute adverse events, nephrogenic systemic fibrosis and brain retention

“…Aus diesen Erkenntnissen der Gadolinium-Retention im Gehirn resultieren viele Fragen, die gegenwärtig untersucht werden. Diese beschäftigen sich damit, wie Gadolinium Zugang zu erkranktem und vor allem gesundem Hirngewebe erhält und wie Gadolinium das Hirngewebe wieder verlässt [40]. Hierbei spielen offensichtlich perivaskuläre Räume, wie periarterielle und pialegliale Pfade (das sogenannte glymphatische System), eine wesentliche Rolle [41].…”

“…After gadolinium has been dissolved out of the linear GBCA, it binds to macromolecules [38]; due to their high relaxivity, these macromolecular compounds are responsible for the hyperintensity on T1-weighted images [39]. These findings of gadolinium retention in the brain give rise to many questions currently under investigation; these deal with how gadolinium gains access to diseased and above all healthy brain tissue, and how gadolinium exits the brain tissue [40]. Obviously, perivascular spaces, such as periarterial and pial-glial pathways (the so-called glymphatic system), play an essential role [41].…”