Applications Of Magnetic Resonance Imaging And In Vivo Spectroscopy In Transgenic Mice Modeling Alzheimer's Disease

Alzheimer disease (AD) is one of the most common neurodegenerative diseases , which is characterized by amyloid-βplaques, neurofibrillary tangles, decreased synaptic density and loss of neurons. The main research work described here was focused on the microstructure and the level of the metabolite in the brain of AD transgenic mice by using magnetic resonance imaging (MRI) and in vivo magnetic resonance spectroscopy (1H MRS) in combination with histopathology and immunohistochemistry. At the same time, we investigated the influence of mice genetype on some usual MR parameter(T₂ value and ADC value).In the first part, APPswe/PS1ΔE9 double transgenic mice that obtained from Jackson lab were transmited and bred, and the genetype of mice were identified by PCR reaction. Using the T₂-weighted multislice multiecho sequence and DWI sequence, the T₂ value and apparent diffusion coefficient were measured in different brain areas. After MR scan, histology staining about senile plaques and iron were performed on the transgenic mice brain aged 4mon and 8mon. The results demonstrated that T₂ value in cortex and hippocampus of double transgenic mice was decreased compared with the wild type mice. There was no difference in the T₂ value in other brain(thalamus,corpus callosum,striatum) areas between double transgenic and wild type mice.The changes of ADC were similar to the T₂ value. The ADC in cortex and hippocampus of double transgenic mice was also decreased compared with the wild type mice. There was no difference in the ADC in the striatum between double transgenic and wild type mice. The result of histology staining shown that senile plaques could be detected in the cortex and hippocampus of double transgenic mice aged 4 mon and 8mon. There was an overall increase in number and area of senile plaques with age. The result of the iron staining shown further that the iron deposition in the basal ganglia of the transgenic mice is similar to the wildtype. But only in the cortex and hippocampus of transgenic mice,we could observe the brown deposition of iron. Iron distribution in the brain of transgenic mice is similar to the senile plaques.There was no iron deposition in the cortex and hippocampus of wild type mice.All these results demostrated that the mice genetype have influences on the MR phenotype,And The decrease of the T₂ value in cortex and hippocampus of double transgenic mice were attributed to iron in senile plaque.However The reduction of ADC parallels the formation of amyloid plaques that causes a decrease of water molecular diffusion ability and might be attributable to the pronounced gliosis associated with the amyloid deposits.In the second part,we investigated the high-resolution magnetic resonance imaging of mouse brain of AD transgenic mice. By using high-resolution magnetic resonance imaging in ex vivo brains of APPswe/PS1ΔE9 double transgenic mice.and in vivo brains of PDAPP mice,we found that the CNR and SNR of ex vivo brain were higher than in vivo brain. The MR images shown that some black spots were visible in the hippocampus and cerebral cortex of the AD transgenic mice and some spots were confirmed by histological sections of the senile plaques and iron in plaques that followed. So, the high-resolution magnetic resonance imaging of senile plaques may be helpful for diagnosis of AD earlier.In the third part, In vivo 1H-MRS was performed on hippocampus of brain of APPswe/PS1ΔE9 double transgenic mice and wild type littermates aged 5,8,12,16 mon using a 4.7T magnet..The levels of N-acetylaspartate(NAA) were lower in transgenic mice as compared to wild type mice at the age of the same months and the level of tg mice at 16 months was significantly reduced. The result described above shown that Proton magnetic resonance spectroscopy (1H MRS) provides a noninvasive way to investigate in vivo neurochemical abnormalities dynamically. The results of the serial MRI and histological staining undoubtedly enriched our understanding of the phenotype of AD transgenic mice, and thus should facilitate the application of MRI techniques to the pathological research and preclinical therapeutic assessments of AD.