3315

Amide proton transfer in amyotrophic lateral sclerosis
Zhuozhi Dai1,2, Sanjay Kalra1, Dennell Mah1, Peter Seres1, Gen Yan3, Hongfu Sun4, Zhiwei Shen5, Renhua Wu5, and Alan H. Wilman1

1University of Alberta, Edmonton, AB, Canada, 2Radiology, 2nd Affiliated Hospital of Shantou University Medical College, Shantou, China, 3Affiliated Hospital of Jiangnan University, Wuxi, China, 4Hotchkiss Brain Institute, Calgary, AB, Canada, 52nd Affiliated Hospital of Shantou University Medical College, Shantou, China

Synopsis

There is lack of objective imaging indicators for ALS diagnosis and assessment. Our hypothesis is that amide is altered due to neurodegeneration in ALS, and this alteration will be visible on APT images. This study aims to explore the value of APT in ALS patients as a possible image biomarker of disease. Thirty-two participants were recruited as part of the Canadian ALS Neuroimaging Consortium. This study first demonstrated changes of APT in the motor cortex and corticospinal tract of ALS patients. The combination of APT and DTI can simultaneously detect changes of metabolism and microstructure in ALS patients.

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease characterized by the death of neurons controlling voluntary muscle movement. There is lack of objective imaging indicators for ALS diagnosis and assessment1. Amide proton transfer (APT) is a novel imaging technique which can detect amide metabolic changes in the brain2-4. The change of amide can be a critical indicator for diverse diseases5. Our hypothesis is that amide is altered due to neurodegeneration in ALS, and this alteration will be visible on APT images. This study aims to explore the value of APT in ALS patients as a possible image biomarker of disease.

METHODS

Patients: This study had institutional review board approval, and written informed consent was obtained from all subjects. Thirty-two participants were recruited as part of the Canadian ALS Neuroimaging Consortium (CALSNIC), including 16 ALS patients and 16 healthy controls. Among ALS patients, six subjects were diagnosed as possible ALS, eight were probable, and two were definite, according to the revised El Escorial criteria.

MRI: Brain MR imaging was performed on a 3T Siemens Prisma using a 64-channel receive head coil. Amide proton transfer imaging, diffusion tensor imaging, routine T1- and T2-weighted image, as well as the flip angle map were obtained. The APT sequence was modified from a standard gradient echo sequence, by adding a series of specific pre-saturation pulses at the beginning of the sequence to enable APT. Saturation power was 0.8 μT. Total saturation time was 3000 ms with duty cycle = ~94%. Other parameters included: TR = 5000 ms; TE = 1.31 ms; centric phase encoding; slice thickness = 6 mm; number of averages =1; FOV = 192 × 192 mm2; matrix = 128 × 128. Parameters for DTI were: TR = 8000 ms; TE = 60 ms; slice thickness = 2 mm (no gap); number of averages =1; matrix = 128 × 128; b1 = 1000 s/mm2, b2 = 2000 s/mm2; diffusion-encoding gradients applied in 30 noncollinear directions.

Processing: All image data was processed in Matlab using in-house software. The Z-spectrum was plotted by normalizing the different offset images to the thermal-equilibrium image. A B0 map was generated and calibrated by the Water Saturation Shift Referencing (WASSR) technique6. For diffusion, Fractional Anisotropy (FA) and Apparent Diffusion Coefficient (ADC) maps were generated by the default processing in the scanner.

Statistical analysis was performed on SPSS 24.0 (IBM, Armonk, NY). The normal distribution test was performed on each parameter first, and all parameters were confirmed to be normality. Then, analysis of covariance (ANCOVA) was used to compare APT, FA, and ADC between patients and healthy controls, and in different regions within ALS patients. The results were reported as mean ± standard deviation and p values less than 0.05 were considered statistically significant.

RESULTS and DISCUSSION

Within ALS patients, the amide peak was significantly different between the motor cortex and other grey matter territories (Fig. 1). Compared with healthy controls, the APT signal intensities in ALS were significantly reduced in motor cortex (P < 0.001) and corticospinal tract (P = 0.046), which was undetectable under routine imaging methods (Fig. 2). There were no statistical differences in temporal cortex (P = 0.449) and medulla (P = 0.342) between patients and controls in APT values. Although the actual type of amide losses caused by neuron death remains to be determined, previous studies supposed that it may be mediated by specific signaling pathways such as programmed cell death.

Compared with the healthy control group, fractional anisotropy (FA) values were reduced in both the corticospinal tract (P = 0.024) and temporal white matter (P = 0.001) in ALS patients. Apparent diffusion coefficient (ADC) was increased in motor cortex (P = 0.008), and the corticospinal tract (P = 0.013) in ALS patients (Fig. 3). The cerebral pathologic hallmark of ALS is the loss of upper motor neurons in the motor cortex, axonal degeneration of the corticospinal tract and lower motor neurons in the brain stem7. In agreement with pathologic findings and previous DTI studies, the decrease of FA and increase of ADC were found in the corticospinal tract in ALS patients1,8. In addition, APT was negatively correlated with FA (r = -0.477, P = 0.006) and positively correlated with ADC (r=0.629 and P < 0.001).

CONCLUSION

To our knowledge, this is the first study demonstrating changes of APT in the motor cortex and corticospinal tract of ALS patients, which has the potential to be an objective imaging biomarker for ALS diagnosis. The combination of APT and DTI can simultaneously detect changes of metabolism and microstructure in ALS patients.

Acknowledgements

Grateful acknowledgment is made to Dr. Mark D Pagel from MD Anderson Cancer Center and Dr. Edward A. Randtke from University of Arizona for technical assistance with pulse sequence implementation. This study was supported in part by grants from Canadian Institutes of Health, the ALS Society of Canada and Brain Canada, the Natural Science Foundation of China (NSFC 81471730, 31870981), and the Natural Science Foundation of Guangdong Province (2018A030307057).

References

1. Menke, R. A., Agosta, F., Grosskreutz, J., Filippi, M. & Turner, M. R. Neuroimaging endpoints in amyotrophic lateral sclerosis. Neurotherapeutics 14, 11-23 (2017).

2. Zhou, J., Lal, B., Wilson, D. A., Laterra, J. & van Zijl, P. Amide proton transfer (APT) contrast for imaging of brain tumors. Magnetic Resonance in Medicine 50, 1120-1126 (2003).

3. Zhou, J. et al. Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nature medicine 17, 130-134 (2011).

4. Dai, Z. et al. Quantitative pH using chemical exchange saturation transfer and phosphorous spectroscopy. International Society of Magnetic Resonance in Medicine 24th Annual Meeting (2016).

5. Jones, K. M., Pollard, A. C. & Pagel, M. D. Clinical applications of chemical exchange saturation transfer (CEST) MRI. Journal of Magnetic Resonance Imaging 47, 11-27 (2018).

6. Kim, M., Gillen, J., Landman, B. A., Zhou, J. & van Zijl, P. C. M. Water saturation shift referencing (WASSR) for chemical exchange saturation transfer (CEST) experiments. Magnetic Resonance in Medicine 61, 1441-1450 (2009).

7. Hughes, J. Pathology of amyotrophic lateral sclerosis. Advances in neurology 36, 61-74 (1982).

8. Zhang, F. et al. Altered white matter microarchitecture in amyotrophic lateral sclerosis: A voxel-based meta-analysis of diffusion tensor imaging. NeuroImage: Clinical 19, 122-129 (2018).

Figures

Figure 1. The Z-spectrum of motor cortex (blue) and control temporal cortex (red) in the healthy control group (A) and ALS patients (B). Five peaks were detected in the Z-spectrum, and each peak could be appropriately fitted using Lorentz fitting. Amide peak was evident and detectable at around 3.5 ppm (zoomed-in region). In ALS patients (B), amide peaks were significantly different between motor cortex and control cortex, whereas they remained constant in control group (A).

Figure 2. Conventional T2- and T1-weighted images, DTI, and APT are shown in both healthy control group and ALS patients. There were no observable lesions in the ALS patient in conventional images. Even in FA and ADC images, ALS and healthy control group could not see a significant difference. However, in the APT images, the differences were noticeable both within the same ALS and between the ALS patients and the healthy controls. The APT signal intensity of motor cortex was significantly degraded in ALS patients.

Figure 3. The bar graphs of FA (A) and ADC (B) in ALS and controls. Compared with the healthy control group, FA values were declined in both corticospinal tract (CT) (P = 0.024) and temporal white matter (TW) (P = 0.001) in ALS patients. While ADC values were increased in motor cortex (MC) (P = 0.008), temporal cortex (TC) (P = 0.009), and corticospinal tract (CT) (P = 0.013) in ALS patients.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
3315