Introduction

Neurodegenerative diseases, such as HD, are irreversible and associated with neuronal impairment that seriously impedes people's daily life. To date, the detailed molecular mechanism remains largely unclear. Occlusion formation and metabolic defects have been considered as biomarkers of neurodegenerative disease.(1-5) Earlier studies have shown that brain glucose utilization and energy metabolism impairment are associated with early abnormalities of neurodegeneration. To clarify the effects of dysregulated metabolites on neurodegenerative disease and the dynamic regulation of glucose in the brain, we aim to develop a tool that can monitor these changes during disease progression in vivo. Chemical exchange saturation transfer (CEST) imaging has been actively developed for more than 15 years,(6-8) and it has been translated to clinical applications recently.(9-11) The most important feature of CEST imaging is its ability to observe the functional groups on metabolites, which reflect the concentration changes at the microscopic scales in the images contrast at macroscopic scales. However, most applications of CEST imaging involve only the CEST-induced changes in the image to locate lesions. There are only a few studies focusing on the connection between metabolites and disease mechanisms. The goal of this study is to utilize CEST imaging to investigate the metabolic dynamics and accumulation status of glucose in the brain of mice with Huntington’s disease (HD). Based on the results of CEST imaging, pathological and biochemical approaches will be used to explore the underlying mechanisms during disease progression in HD mice. The CEST imaging approach is expected to provide a more effective, inexpensive and non-invasive diagnostic method for studying neurodegenerative diseases.

Method

R6/2 HD mice were used for the study. All images were acquired with a Bruker Biospin® 7 T MRI Scanner outfitter with a 20-mm-bore. A CEST-RARE sequence was used to acquire CEST image at +1.2 ppm from water resonance frequency with the following parameters: repetition time (TR) = 2000 ms, effective echo time (TE) = 56 ms, RARE factor = 23, field-of-view (FOV) =f 3.5 × 3.5 cm, acquisition matrix size = 256 x 32, and image resolution = 0.014x 0.027 cm/pixel. The length of the CW pulse is 3000 ms, and the B1 field is 1.6 μT.

Results and discussion

Dynamic glucose-enhanced (DGE) images, detected by CEST, report on the exchange of the glucose OH group proton with water protons and provide direct information on glucose metabolism. It also provides the spatial distribution of the metabolic processes. Glucose (50[C1] % solution) was injected 10 min after the start of MRI scan, and the time-dependent signal variation in the image was observed, as shown in Fig. 1. The DGE mice brain images reveal that HD mice uptake less glucose than WT mice. Figure 2 shows the glucose concentration variation in the striatum as a function of time of HD and WT mice of different ages. It shows that the glucose uptake in the HD mice striatum decreases with age. The groups of older than 9-11 weeks HD mice were easy to find the symptoms of HD, and their glucose uptaking also show a significant decrement. By contrast, WT mice show a mild decrease in the glucose uptake for the mice with similar age.

Conclusions

Glucose metabolism in neurodegenerative diseases, such as HD, is a critical issue in the disease progress. The dynamic variation of glucose uptake by DGE imaging can reveal the real situation of the glucose metabolism in the brain. The application of HD mice model shows a significant decrement in the HD mice.

Acknowledgements

We thank the excellent technical assistant of the Animal Imaging Facility at Academia Sinica (Taiwan) for their assistance with the MRI measurements. We are also appreciative of the HD mice model provided by Dr. Yijuang Chern and her constructive discussion of the HD study.

References

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