**4.3 Effect in the central nervous system (CNS)**

Gd3+ affects the development of infant CNS: In our previous study, we reported that Gd was transferred to pups and was retained in their brain during postnatal period. The perinatal exposure to GBCAs induced behavioral changes in mice; gadodiamide (Omniscan) had a more severe effect than gadoterate meglumine (Dotarem). All pups were separated from mothers for weaning on P21, and the total Gd in the brain of mothers and pups were measured on P28. Higher dose of Gd retention was found in mothers and pups in the linear-type group. Perinatal administration of GBCAs caused anxiety-like behaviors, disrupted motor coordination, impaired memory function, stimulated tactile sensitivity, and decreased muscle strength, especially in the gadodiamide-treated group [48]. In linear GBCA group, the total Gd retention in the brain of the mothers and the pups was higher than in the macrocyclic group. Both GBCAs were intravenously injected with 2 mmol/kg into the mothers from E15 to E19, which is the critical period for the development of neuronal circuits in fetus. According to the results of this study, we investigated Gd retention in various organs in both the mother and pup mice models [49]. Gd retentions in mother mice were consistently higher after gadodiamide (Omniscan) administration than gadoterate meglumine (Dotarem). Moreover, significantly

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.

### **4.4 Glymphatic system**

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 before 4 h [52].

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

### **Figure 9.**

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

**61**

*Current Clinical Issues: Deposition of Gadolinium Chelates*

organs in linear type than those in macrocyclic GBCAs.

nucleus varies according to the type of administered GBCA. In addition, the distribution of gadolinium cannot be explained by passive transportation. The accumulation of GBCA in the brain is probably due to some extent to the glymphatic system, but any association between the glymphatic system and signal hyperintensity of the

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

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

The authors would like to thank Achmad Adhipatria P. Kartamihardja, Khongorzul Erdene, Miski Aghnia Khairinisa, and Odgerel Zorigt for their researches. This article is based on many researchers' great works and our colleagues' experiments. We also thank Nobuko Kemmotsu for editing our manuscript with English correction. Our colleagues have graduated from Gunma University Graduate School of Medicine, and they came from Asian countries to Japan to join our program, "Asian Nuclear Medicine Graduate Program (ANMEG Program)." This program was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of the Japanese government. The mission of this program is to train specialists in nuclear medicine and radiology in medical fields who will become leading clinicians and researchers, both in their home countries and at an international level. The ANMEG program and MEXT supported them during their

The authors have no conflicts of interest directly relevant to the content of this

*DOI: http://dx.doi.org/10.5772/intechopen.91260*

dentate nucleus remains obscure.

**5. Conclusion**

function.

stay in Japan.

article.

**Conflict of interest**

**Acknowledgements**

nucleus varies according to the type of administered GBCA. In addition, the distribution of gadolinium cannot be explained by passive transportation. The accumulation of GBCA in the brain is probably due to some extent to the glymphatic system, but any association between the glymphatic system and signal hyperintensity of the dentate nucleus remains obscure.
