As a model for guanidinoacetate methyltransferase (GAMT) deficiency in humans, a gene knockout mouse model was generated. Here we report on several metabolic abnormalities in these mice, observed by in vivo and in vitro MR spectroscopy. In 1 H MR spectra of brain and hindleg muscle a clearly reduced signal of creatine (Cr) was observed in GAMT-deficient (GAMT-/-) animals. Analysis of the 1 H MR spectra of GAMT-/-brain indicated little or no increase of a signal for guanidinoacetate (Gua). In proton MR spectra of muscle, a broad signal of low intensity was observed for Gua. However, substantial Gua accumulation in intact muscle tissue was unequivocally confirmed in high-resolution magic angle spinning spectra, in which the Gua signal was resolved as one clear sharp singlet. In 31 P MR analysis of brain and hindleg muscle a strongly reduced phosphocreatine (PCr) content was shown. In addition, a signal of phosphorylated Gua at 0.5 ppm upfield of PCr was observed, with much higher intensity in muscle than in brain. This signal decreased when ischemia was applied to the muscle and recovered after ischemia was released. Overall, the in vivo 31 P and 1 H MR spectroscopy of GAMT-/-mice is similar to that of human GAMT deficiency. This opens up new avenues for the fundamental study of tissue-type dependence of creatine synthesis and transport and for diagnostic and therapeutic aspects of creatine deficiencies in humans. Magn Reson Med 50: 936 -943, 2003.

The effects of creatine (Cr) absence in skeletal muscle caused by a deletion of guanidinoacetate methyltransferase (GAMT) were studied in a knockout mouse model by in vivo 31 P magnetic resonance (MR) spectroscopy.31 P MR spectra of hindleg muscle of GAMT-deficient (GAMT-/-) mice showed no phosphocreatine (PCr) signal and instead showed the signal for phosphorylated guanidinoacetate (PGua), the immediate precursor of Cr, which is not normally present. Tissue pH did not differ between wild-type (WT) and GAMT-/-mice, while relative inorganic phosphate (P i ) levels were increased in the latter. During ischaemia, PGua was metabolically active in GAMT-/-mice and decreased at a rate comparable to the decrease of PCr in WT mice. However, the recovery rate of PGua in GAMT-/-mice after ischaemia was reduced compared to PCr in WT mice. Saturation transfer measurements revealed no detectable flux from PGua to γ-ATP, indicating severely reduced enzyme kinetics. Supplementation of Cr resulted in a rapid increase in PCr signal intensity until only this resonance was visible, along with a reduction in relative P i values. However, the PGua recovery rate after ischaemia did not change. Our results show that despite the absence of Cr, GAMT-/-mice can cope with mild ischaemic stress by using PGua for high energy phosphoryl transfer. The reduced affinity of creatine kinase (CK) for (P)Gua only becomes apparent during recovery from ischaemia. It is argued that absence of Cr causes the higher relative P i concentration also observed in animals lacking muscle CK, indicating an important role of the CK system in P i homeostasis.

A new coil design for sensitivity-enhanced 13 C MR spectroscopy (MRS) of the human brain is presented. The design includes a quadrature transmit/receive head coil optimized for 13 C MR sensitivity. Loss-less blocking circuits inside the coil conductors allow this coil to be used inside a homogeneous circularly polarized 1 H B 1 field for 1 H decoupled 13 C MRS. A quadrature 1 H birdcage coil optimized for minimal local RF heating makes broadband 1 H decoupling in the entire human brain possible at 3 Tesla while remaining well within international safety guidelines for RF absorption. Apart from a substantial increase in sensitivity compared to conventional small linear coils, the quadrature 13 C coil combined with the quadrature 1 H birdcage coil allows efficient cross polarization (CP) in the brain, resulting in an additional 3.5-fold sensitivity improvement compared to direct 13 C measurements without nuclear Overhauser enhancement (NOE) or polarization transfer. Combined with the gain in power efficiency, this setup allows broadband 1 H to 13 C CP over large areas of the brain.

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The new MR compatible manipulator can be used safely for patient care. It showed a high accuracy and short total procedure time, demonstrating great potential to improve the transrectal prostate biopsy procedure.