**4.2 Gadolinium deposition in the brain (Kanda reports)**

In 2014, Kanda et al. reported unusual brain MRI findings in patients with a history of various GBCAs administration [43] (**Figures 7** and **8**). High signal intensity of the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images was seen in patients with frequent administrations of GBCAs. Signal intensities on T1WI showed a positive correlation with the number of previous GBCA administrations, even in patients with normal renal function. Furthermore, the positive correlation with numbers of GBCA administrations and signal intensities on T1WI was noted only for patients with linear GBCA administrations, while no correlations were seen in patients with macrocyclic GBCA administrations [15, 44, 45]. Several researchers also reported a presence of hyperintensity in the dentate nucleus that corresponded with the number of past linear GBCAs administrations [46, 47]. Similar findings were reported in pediatric patients [30, 43].

The cause of high signals in the globus pallidus continues to be a hot topic in this field. Cadaver studies with quantitative analyses using mass spectroscopy revealed high signal intensities of the globus pallidus in patients with frequent GBCA administrations would be based on gadolinium. Although high signal intensities in the globus pallidus have been also observed in patients who have a history of liver failure, Wilson disease, Osler-Weber-Rendu disease, manganese toxicity, calcification, hemodialysis, total parenteral nutrition, and neurofibromatosis type 1, various kinds of metal ions would be deposited in the globus pallidus. However, the forms of gadolinium deposition have not been known whether chelate type,

### **Figure 7.**

*Unenhanced T1-weighted MR image. Signal increase on unenhanced T1-weighted MR image in the basal ganglia, which is indicated by* arrowheads*.*

**59**

bound to gadolinium.

**Figure 8.**

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

*nucleus of the cerebellum, which is indicated by arrowheads.*

*Current Clinical Issues: Deposition of Gadolinium Chelates*

gadolinium ions, and phosphate or other complexes. In serum or blood, gadolinium ion released from GBCAs tends to bind to phosphate quickly and to make a form of phosphate complex with gadolinium. Since phosphate complex has no signals on MRI, phosphate complex would not be a cause of high signals in the globus pallidus. In our speculation, macromolecules of gadolinium bound to protein would be one of the candidates for deposition in the brain. The reason for our speculation is that gadolinium ions bound to macromolecules show much brighter signals on T1WI than those of small molecules, which is based on the model known as the Solomon-Bloembergen-Morgan formula. Since the macromolecule rotates slowly compared with small molecules, the contact time with gadolinium and water proton can be prolonged, and the T1 shortening effect of gadolinium can be increased. The high signals in the globus pallidus would be derived from the role of macromolecules

*Unenhanced T1-weighted MR image. Signal increase on unenhanced T1-weighted MR image in the dentate* 

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

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

*Current Clinical Issues: Deposition of Gadolinium Chelates DOI: http://dx.doi.org/10.5772/intechopen.91260*

### **Figure 8.**

*Rare Earth Elements and Their Minerals*

or Gd-DTPA-BMA to retain bone.

**4.2 Gadolinium deposition in the brain (Kanda reports)**

Similar findings were reported in pediatric patients [30, 43].

gadolinium behind in bone than did ProHance (Gd-HP-DO3A). These results would indicate two important issues: (1) chelate stability and (2) affinity of GBCA to the bone. Linear GBCAs like Omniscan (Gd-DTPA-BMA) would release more Gd3+ ions than macrocyclic GBCAs like ProHance (Gd-HP-DO3A). Since the bone is a known natural repository for unchelated Gd3+ ions, free Gd3+ ions released from Omniscan (Gd-DTPA-BMA) would retain bone. Another reason to deposit gadolinium to bone would be the affinity of GBCAs to bone. Hydroxyapatite structure is similar to the structure of DTPA. It might be one of causes for linear GBCAs, especially Gd-DTPA

In 2014, Kanda et al. reported unusual brain MRI findings in patients with a history of various GBCAs administration [43] (**Figures 7** and **8**). High signal intensity of the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images was seen in patients with frequent administrations of GBCAs. Signal intensities on T1WI showed a positive correlation with the number of previous GBCA administrations, even in patients with normal renal function. Furthermore, the positive correlation with numbers of GBCA administrations and signal intensities on T1WI was noted only for patients with linear GBCA administrations, while no correlations were seen in patients with macrocyclic GBCA administrations [15, 44, 45]. Several researchers also reported a presence of hyperintensity in the dentate nucleus that corresponded with the number of past linear GBCAs administrations [46, 47].

The cause of high signals in the globus pallidus continues to be a hot topic in this field. Cadaver studies with quantitative analyses using mass spectroscopy revealed high signal intensities of the globus pallidus in patients with frequent GBCA administrations would be based on gadolinium. Although high signal intensities in the globus pallidus have been also observed in patients who have a history of liver failure, Wilson disease, Osler-Weber-Rendu disease, manganese toxicity, calcification, hemodialysis, total parenteral nutrition, and neurofibromatosis type 1, various kinds of metal ions would be deposited in the globus pallidus. However, the forms of gadolinium deposition have not been known whether chelate type,

*Unenhanced T1-weighted MR image. Signal increase on unenhanced T1-weighted MR image in the basal* 

**58**

**Figure 7.**

*ganglia, which is indicated by* arrowheads*.*

*Unenhanced T1-weighted MR image. Signal increase on unenhanced T1-weighted MR image in the dentate nucleus of the cerebellum, which is indicated by arrowheads.*

gadolinium ions, and phosphate or other complexes. In serum or blood, gadolinium ion released from GBCAs tends to bind to phosphate quickly and to make a form of phosphate complex with gadolinium. Since phosphate complex has no signals on MRI, phosphate complex would not be a cause of high signals in the globus pallidus. In our speculation, macromolecules of gadolinium bound to protein would be one of the candidates for deposition in the brain. The reason for our speculation is that gadolinium ions bound to macromolecules show much brighter signals on T1WI than those of small molecules, which is based on the model known as the Solomon-Bloembergen-Morgan formula. Since the macromolecule rotates slowly compared with small molecules, the contact time with gadolinium and water proton can be prolonged, and the T1 shortening effect of gadolinium can be increased. The high signals in the globus pallidus would be derived from the role of macromolecules bound to gadolinium.
