**5. Conclusion**

*Rare Earth Elements and Their Minerals*

**4.4 Glymphatic system**

before 4 h [52].

higher Gd retention was observed in the organs of pups after whose mothers were administered gadodiamide (Omniscan) than gadoterate meglumine (Dotarem) (**Figure 9**). The results indicated that the linear GBCA affected not only the brain but also other maternal organs, such as the bone, spleen, and liver. Though the effects of maternal GBCA administration have not been reported in humans, our studies would warn the potential risk of using GBCAs in pregnant women.

The glymphatic system is discovered as a brain waste system to transport low molecular weight materials from the cerebrospinal fluid (CSF) to the interstitial fluid (ISF). The glymphatic system may also transport GBCAs to the brain. Ilif et al. examined GBCA deposition in the brain with rat by MRI [50]. When GBCA was injected into the rat subarachnoid space, it moved along the basilar artery into the brain parenchyma. In addition, Eide et al. evaluated patients who had GBCA administrations in the subarachnoid space with MRI [51]. Four hours after GBCA administration in the subarachnoid space, both the cortical and white matter of the brain showed high signal intensities, and the gadolinium entrance to the human brain through the glymphatic system was speculated. Naganawa et al. reported that on post contrast FLAIR image, the subarachnoid space and perivascular space showed increased signal intensities and GBCA transfer to the subarachnoid space and perivascular space on brain MRI of 27 subjects who had administrated GBCA

These results demonstrated that even in patients with normal renal function, intravenously administered GBCA can be transported through the glymphatic system and reach the brain. However, the association between the hyperintensity in the globus pallidus and dentate nucleus and the GBCA that is transported through the glymphatic system is still unclear. The glymphatic system transports all low molecular weight materials passively, and both the linear type of GBCA and macrocyclic GBCA are transported in the same way. However, the signal intensity of the dentate

*Gadolinium depositions in organs of mother mice and their pups. The gadolinium concentrations in the organs of mice with the administration of linear GBCA (Gd-DTPA-BMA) were higher than those of macrocyclic* 

**60**

**Figure 9.**

*GBCA (Gd-DOTA) [49].*

We discussed two types of GBCAs: linear chelates and macrocyclic chelates. The macrocyclic GBCAs are more stable than the linear types because free Gd ions do not get released from the macrocyclic chelates easily in various conditions. Many preclinical and clinical studies have revealed higher deposition of Gd in the body organs in linear type than those in macrocyclic GBCAs.

Special precaution needs to be taken in cases of chronic kidney disease or patients with renal dysfunction as the only route of excretion of the GBCAs is via the kidney. Nephrogenic system fibrosis (NSF) has been noted in such renal function-impaired patients who had been administered GBCAs, especially linear types. Moreover, linear GBCAs are easy to release Gd ions from chelates. Linear GBCAs have a tendency to be deposited in the human body, including brain tissue. The use of macrocyclic GBCAs should be recommended even for patients with normal renal function.
