Role of myo-inositol by magnetic resonance spectroscopy in early diagnosis of Alzheimer's disease in APP/PS1 transgenic mice

Abstract

Background/aims: To explore the potential value of myo-inositol (mIns), which is regarded as a biomarker for early diagnosis of Alzheimer's disease, in APP/PS1 transgenic (tg) mice detected by (1)H-MRS.

Methods: (1)H-MRS was performed in 30 APP/PS1 tg mice and 20 wild-type (wt) littermates at 3, 5 and 8 months of age. Areas under the peak of N-acetylaspartate (NAA), mIns and creatine (Cr) in the frontal cortex and hippocampus were measured, and the NAA/Cr and mIns/Cr ratios were analyzed quantitatively.

Results: Compared with the wt mice, the mIns/Cr ratio of the 3-month-old tg mice was significantly higher (p < 0.05), and pathology showed activation and proliferation of astrocytes in the frontal cortex and hippocampus. The concentration of NAA was significantly lower at 8 and 8 months of age (p < 0.05). According to the threshold of mIns/Cr that was adopted to separate the tg from the wt mice, the rate of correct predictions was 82, 94 and 95%, respectively, for 3, 5 and 8 months.

Conclusion: Of the early AD metabolites as detected by (1)H-MRS, mIns is the most valuable marker for assessment of AD. Quantitative analysis of mIns may provide important clues for early diagnosis of AD.

Fig. 1

Localized proton MRS of mice brains in vivo. The region of interest (ROI) was selected in the left side of the mouse brain, including the hippocampus and part of the frontal cortex. ROI sizes were approximately 2.0 × 2.0 × 2.0 mm.

Fig. 2

Spectra from the hippocampus and frontal cortex in tg (top) and in wt mice (bottom) at the age of 3 months. mIns was significantly increasing in the tg mice, and there was no significant change in NAA.

Fig. 3

Spectra from the hippocampus and frontal cortex in tg (top) and in wt mice (bottom) at the age of 5 months. The NAA/Cr ratios of the tg mice decreased significantly.

Fig. 4

Spectra from the hippocampus and frontal cortex in tg (top) and in wt mice (bottom) at the age of 8 months. There were more remarkable changes for mIns and NAA in the tg mice.

Fig. 5

GFAP fluorescent staining. a Expression of GFAP in the hippocampus of 3-month-old wt mice. Immunofluorescence FITC staining. × 200. b In the hippocampus of 3-month-old tg mice, reactive astrocytes had a larger appearance than in wt mice. The activated astrocytes displayed an altered size and morphology. Immunofluorescence FITC staining. × 200. c GFAP-positive cells were seen interlocking into masses in 8-month-old tg mice. Immunofluorescence FITC staining. × 400.

Fig. 6

Aβ staining. a No Aβ plaques were seen in the observation areas of 3-month-old tg mice. Immunohistochemical staining. × 200. b In 5-month-old tg mice, there were small, scattered brown (arrows) deposits in the hippocampus. Immunohistochemical staining. × 200. c In higher magnitude, a neuritic plaque was seen in the observation areas of 8-month-old tg mice. Immunohistochemical staining. × 400.

Fig. 7

Nissl's staining (immunohistochemical staining, × 400). a Neurons were seen in dense arrangement, and the Nissl bodies were rich in cytoplasm in the hippocampus of 3-month-old tg mice. b Arrangement of neurons is sparse, and there was slight neuronal shrinkage in the hippocampus of 5-month-old tg mice. c Nissl bodies in the cytoplasm decreased or disappeared in the hippocampus of 8-month-old tg mice.