Study of regional metabolites by quantitative proton MR spectroscopy in APP/PS1 double transgenic Alzheimer disease mice

Objective: To explore changes of metabolites in APP/PSI double transgenic mice of Alzheimer disease (AD) by 1H-MR spectroscopy (1H-MRS) and the application value of in early diagnosis of AD. Methods: 1H-MRS was performed in 35 APP/PS1 transgenic mice of AD (study group) and 20 wild type mice (control group) at age of 3, 6 and 9 months using a 7.0 T MR system. Sub-peak areas of N-acetyl aspartate (NAA), myo-inositol (mI) and creatine (Cr) in the cerebral cortex and hippocampus were measured, and the NAA/Cr and mI/Cr ratios were calculated. The changes in pathology between the two groups were compared. Using the lower limit of 95% confidence interval (CI) of the mI/Cr ratio and the upper limit of 95% CI of the NAA/Cr ratio of AD mice as the threshold, their influences on sensitivity, specificity and accuracy of various age groups of AD animals were compared. Comparison of the 1H-MRS indexes between study mice and wild type mice at each time point were conducted by a two-sample t test. Results: The mean mI/Cr ratios of AD mice were 0.68 ± 0.03, 0.72 ± 0.04, and 0.77 ± 0.04 respectively at 3, 6 and 9 months of age; while they were 0.63±0.04, 0.64±0.03, and 0.64±0.04 respectively in control group, the difference was significant (t=2.814, 5.146, 14.437, P<0.01). Compared with the control group, the mI/Cr ratio of the 3-month-old AD mice of the study group was significantly increased, and histological examination showed proliferation and activation of neuroglial cells in the cerebral cortex and hippocampus. The mean NAA/Cr ratio were 1.17±0.08, 1.04±0.05, and 0.90±0.05 respectively at 3, 6 and 9 months of age in study group, while they were 1.18±0.07, 1.16±0.07, and 1.18±0.08 respectively in control group. There were no significant difference (t=0.752, P>0.05) between the study group and control group at S months of age, and the NAA/Cr ratio decreased significantly only at 6 and 9 months of age (t=-8.514, -5.646, P<0.01). The immunohistochemical exam demonstrated the appearance of Aβ plaque. According to threshold of mI/Cr, the sensitivity of AD mice of 3, 6 and 9 months of age was 80% (28/35), 84% (26/31) and 85% (23/27), and the specificity was 85% (17/20), 94% (17/18) and 100% (16/16), and the accuracy was 82% (45/55), 88% (43/49) and 91% (39/43), respectively. For NAA/Cr, the sensitivity of AD mice of 6 and 9 months of age was 84% (26/31) and 89% (24/27), and the specificity was 89% (16/18) and 100% (16/16), and the accuracy was 86% (42/49) and 93% (40/43), respectively. Conclusions: NAA and mi are the most sensitive and specific markers for early assessment of AD, and change of mI is earlier than that of NAA. Quantitative analysis of mi may provide important clues for early diagnosis of AD. (authors)