Glutamate (Glu) is a major excitatory neurotransmitter in brain and has been shown to decrease in the early stages of Alzheimer’s disease (AD). Using glutamate amine exchange saturation transfer (GluCEST) method, we imaged the change in [Glu] in APP-PS1 transgenic mouse model of AD at high spatial resolution. Compared to wild-type controls, AD mice exhibited notable reduction of GluCEST contrast (~30%) in all areas of the brain. The change in [Glu] is further validated through proton magnetic resonance spectroscopy (1HMRS). A positive correlation was observed between GluCEST contrast and 1HMRS measured Glu/total creatine (Glu/tCr) ratio. This method potentially provides a novel noninvasive biomarker for diagnosing the disease in preclinical stages and enables the development of disease modifying therapies for AD.

The fully automated method for assessment of spectral quality provides a valuable tool to support clinical MRSI or spectroscopic MRI studies for use in fields such as adaptive radiation therapy planning.

Glutamate Chemical Exchange Saturation Transfer (GluCEST) MRI was used to measure metabolic changes in mice treated with 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) by mapping regional cerebral glutamate. The GluCEST contrast following MPTP treatment was correlated with 1H MR spectroscopy, motor function and immunohistochemical measures. GluCEST contrast was found to be significantly higher in the striatum and motor cortex of mice treated with MPTP than in controls (p<0.001), which was confirmed by localized 1H MR spectroscopy. Elevated striatal GluCEST was positively associated with local astrogliosis measured by immunohistochemistry for glial fibrillary acidic protein (GFAP). Additionally, a negative correlation was found between the GluCEST of striatum (R = −0.705, p<0.001) and motor cortex (R = −0.617, p<0.01) with motor function measured by the four limb grip strength test, suggesting a role of elevated glutamate in the abnormal cerebral motor function regulation. GluCEST contrast and GFAP staining were unaltered in the thalamus indicating glutamate elevation was localized to striatum and possibly motor cortex. These findings suggest that in addition to measuring spatial changes in glutamate, GluCEST may serve as an in vivo biomarker of metabolic and functional changes that may be applied to the assessment of a broad range of neuropathologies.

Glutamate Chemical Exchange Saturation Transfer (GluCEST) MRI is a recently developed technique to image glutamate. In the present study, we evaluated the reproducibility and background contamination to the GluCEST and source of the GluCEST changes in a mouse model of Parkinson’s disease. Repeated measurements in five mice demonstrated an intra-animal coefficient of variation (CV) of GluCEST signal to be 2.3 ± 1.3% and inter-animal CV of GluCEST to be 3.3 ± 0.3%. Mice were treated with MPTP to create a localized striatal elevation of glutamate. We found an elevation in the GluCEST contrast of the striatum following MPTP treatment (Control: 23.3 ± 0.8%, n = 16; MPTP: 26.2 ± 0.8%, n = 19; p ≤ 0.001). Additionally, the positive association between glutamate concentration measured via 1H MRS and GluCEST signal was used to estimate background contribution to the measured GluCEST. The contribution of signal from non-glutamate sources was found to be ~28% of the total GluCEST. Immunohistochemical analysis of the brain showed co-localization of glutamate with GFAP in the striatum. This suggests that the elevated glutamate present in the striatum in this mouse model reflects astroglial proliferation or reactivity due to the action of MPTP. The potential of GluCEST as a biomarker for imaging inflammation mediated gliosis is discussed.

Abnormal choline metabolism is a hallmark of cancer and is associated with oncogenesis and tumor progression. Increased choline is consistently observed in both pre-clinical tumor models and in human brain tumors by proton magnetic resonance spectroscopy (MRS). Thus, inhibition of choline metabolism using specific choline kinase inhibitors such as MN58b may be a promising new strategy for treatment of brain tumors. We demonstrate the efficacy of MN58b in suppressing phosphocholine production in three brain tumor cell lines. In vivo MRS studies of rats with intra-cranial F98-derived brain tumors showed a significant decrease in tumor total choline concentration after treatment with MN58b. High resolution MRS of tissue extracts confirmed that this decrease was due to a significant reduction in phosphocholine. Concomitantly, a significant increase in poly-unsaturated lipid resonances was also observed in treated tumors, indicating apoptotic cell death. Magnetic resonance imaging (MRI) based volume measurements demonstrated a significant growth arrest in the MN58b-treated tumors in comparison to saline-treated controls. Histologically, MN58b-treated tumors showed decreased cell density, as well as increased apoptotic cells. These results suggest that inhibition of choline kinase can be used as an adjuvant to chemotherapy in the treatment of brain tumors and that decreases in total choline observed by MRS can be used as an effective phamacodynamic biomarker of treatment response.