0484
Phosphorous and Proton MR Spectroscopy Study of Creatine Transporter Deficiency1National Institutes of Health, Bethesda, MD, United States, 2Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Synopsis
The X- linked Creatine Transporter Deficiency (CTD) is one of three types of the cerebral creatine deficiency disorders. It is caused by mutations in the X-linked gene SLC6A8. We report the first combined 31P and 1H MRS study of CTD patients. Relative concentrations of key metabolites were quantitatively analyzed. The PCr/total-phosphate and total-Cr/NAA ratios were found to be markedly reduced in CTD patients. By combining the proton and 31P data we found that the relative reduction in PCr in CTD patients is much less than that of total Cr.
INTRODUCTION
The X- linked Creatine Transporter Deficiency (CTD) is one of three types of the cerebral creatine deficiency disorders. It is caused by mutations in the X-linked gene SLC6A8.1, 2 CTD patients have been evaluated using 1H spectroscopy,1, 3-6 but not by 31P MRS. Here we report the first 31P MRS study of CTD patients in combination with 1H MRS.METHODS
In vivo MRS was performed on a Siemens 3T scanner. 31P spectra were acquired using a 31P surface coil (Dia. = 7 cm) and a half volume proton coil. 1H spectra were obtained using a 20-channel phased array head coil. Twelve CTD patients (all male, age 3-14 years) were recruited through an IRB-approved protocol.
An excite-acquire sequence was used to obtain 31P FIDs from the occipital lobe of eleven CTD patients with TR = 2 s, SW = 5 kHz, data = 1024, NA =128. Unsaturated 31P spectra were collected from five CTD patients with TR = 25 s and NA = 64. 1H MRS was acquired using localized PRESS from a 2x2x2 cm3 voxel centered in the active volume of the 31P coil. TR = 2 s, SW = 2 kHz, data = 2048, NA = 128. 1H spectra with TE = 30 and 135 ms were acquired separately. jMRUI7 and LC Model8 software were used to analyze and quantify metabolites in 31P and 1H spectra, respectively.
RESULTS
Fig 1 shows 31P spectra from two
CTD patients with NA = 128 at TR = 2 s (A) and TR = 25 s (B), respectively. Nine
resonances were clearly detected including α-, β-, γ-ATP, NAD, PCr, PE, PC, Piin and Piex.
The substantial reduction in PCr signal was found to the most pronounced
feature across all patients’ 31P spectra. GPE and GPC were
overlapped by macromolecular phosphate (MP). They were not spectrally resolved
at 3T. Fig 2 shows 1H spectra from a CTD patient at TE = 30 ms (A) and 135
ms (B), respectively. Consistent with previous reports,1, 3-6 total
creatine (Cr + PCr) is markedly decreased in CTD patients. The values of PCr/total-phosphate and total Cr/NAA were listed in Table 1.
DISCUSSION
The doublets of γ-, α-ATP resonances, the NAD and Piex peaks were consistently resolved. The unusual high spectral resolution for CTD patients at 3T is likely due to much less iron in the young patients’ brain, thus less local susceptibility line broadening.
For 1H MRS, the ratio of t-Cr/NAA in CTD patients (0.115 ± 0.012) agreed with values reported in previous studies.5, 6 The value of PCr/total-phosphate for CTD patients at TR = 2 s and 25 s is approximately 24 % and 28 %, respectively, of the corresponding value for adult healthy volunteers (unpublished data).
In unsaturated 31P spectra, PE has the largest signal increase indicating that PE has the longest T1 among 31P metabolites.9 An interesting clinical question is if the PCr/total-Cr ratio is maintained in CTD because PCr has been considered as a high energy phosphate reservior. In adult healthy volunteers (n=3) the (PCr/total-phosphate)/(total-Cr/NAA) ratio was 0.178 ± 0.021 (mean ± SD, n=3, 31P MRS TR = 2 s, unpublished data). In comparison, the (PCr/total-phosphate)/(total-Cr/NAA) ratio of the CTD patients was significantly larger (0.316 ± 0.023, n=11, 31P MRS TR = 2 s, p=0.001). Because total phosphate and NAA remained approximately unchanged, the (PCr/total-phosphate)/(total-Cr/NAA) ratio is a surrogate marker for PCr/total-Cr. Thus, our data indicate that there is a very large increase in PCr/total-Cr in addition to the large reduction in total Cr in CTD patients. The lack of detectable lactate (1.3 ppm) in the TE = 135 ms 1H MRS spectra (see Fig. 2B) indicates that metabolic matching is maintained in CTD with no significant increase in the glycolytic pathway.
CONCLUSION
Our 1H MRS results confirmed previous observation of a large reduction in total Cr in CTD patients. Although 31P MRS spectra of CTD patients also showed a large reduction in PCr, the relative reduction in PCr in CTD patients is much less than that of total Cr as revealed by combined analysis of the proton and 31P MRS data. Furthermore, no detectable lactate signal was observed in the proton MRS spectra of CTD patients. Our results suggest that energy production in the resting brain under impaired creatine transport is predominantly by oxidative metabolism. Since the increased brain energy consumption when responding to a stimulus is initially provided by the high energy phosphate of PCr10 the low availability of PCr in CTD may contribute to many of its symptoms including developmental delay and mental retardation.Acknowledgements
This work is supported by intramural research funds of National Institutes of Healthy.References
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