磁共振成像及活体波谱技术在阿尔茨海默病转基因小鼠中的应用
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摘要
阿尔茨海默病是一种最常见的神经系统变性疾病,其基本的病理学改变是老年斑、神经纤维缠结、突触数目的减少以及神经元的丢失。本研究运用磁共振成像和活体波谱技术,并结合病理学和免疫组织化学技术,对AD转基因小鼠脑组织的微观结构和代谢物的水平进行研究。同时研究了小鼠的基因型对其横向磁豫时间(T_2值)和表观扩散系数(ADC值)的影响。
在本文的第一部分中,我们对所获取的APPswe/PS1ΔE9双转基因小鼠进行了传代,繁殖。并通过PCR反应对小鼠的基因型进行了鉴定。应用多层面多回波SE序列和弥散加权成像(DWI)序列对4-8月龄的转基因和野生型小鼠不同脑区的T_2值和ADC值进行了测量。磁共振扫描完成后,进行老年斑和铁的组织学染色。研究发现,与野生型小鼠相比,转基因小鼠皮质和海马区的T_2值明显降低,而丘脑,胼胝体和纹状体的T_2值变化不大。ADC值的改变也与T_2值的改变相类似,转基因小鼠皮质和海马的ADC值较野生型小鼠为低,而纹状体的ADC值变化不大。组织学染色发现,4月龄及8月龄转基因小鼠的皮质及海马可出现老年斑的沉积,并且随着小鼠月龄的增加,老年斑的数目增多,面积也增大。铁染色进一步发现在转基因及野生型小鼠基底神经节处均可见到铁的沉积。铁在转基因小鼠的皮质及海马处呈棕褐色沉积,并且其分布与老年斑的分布相类似,而野生型小鼠的皮质及海马未见铁的沉积.。这些结果说明:小鼠的基因型会影响到磁共振的表型。转基因小鼠皮质和海马区的T_2值的降低可能与老年斑内的铁有关,而ADC值的降低,除了与老年斑形成引起的水分子的弥散能力减低有关之外,还与继发的神经胶质增生有关。
在本文的第二部分中,我们主要研究了AD转基因小鼠的磁共振的高分辨成像。通过对PDAPP转基因小鼠的活体扫描和APPswe/PS1ΔE9双转基因小鼠的离体扫描发现:离体扫描组织的对比度和信噪比明显较活体扫描为高,在AD转基因小鼠的活体和离体T2WI上的皮质和海马上可见一些点状的低信号区,部分的低信号区可与老年斑和铁染色相对应。这也说明了老年斑的磁共振显微成像可能有助于AD的早期诊断。
在本文的第三部分中,我们对5,8,12,16月龄的APPswe/PS1ΔE9双转基因小鼠的海马进行了活体波谱扫描,结果发现转基因小鼠海马区NAA的含量较同月龄野生型小鼠含量为低,其中16月龄的转基因小鼠海马区内NAA的水平较野生型小鼠下降更为明显。上述结果也提示1H-MRS可作为一种无创性的方法,动态的检测脑内代谢物的水平变化。
总之,一系列MRI实验以及组织学染色的结果更加深了对AD转基因小鼠表型的认识,为MRI技术在AD的发病机制和临床药物的筛选等方面提供了实验基础。
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(T_2 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 T_2-weighted multislice multiecho sequence and DWI sequence, the T_2 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 T_2 value in cortex and hippocampus of double transgenic mice was decreased compared with the wild type mice. There was no difference in the T_2 value in other brain(thalamus,corpus callosum,striatum) areas between double transgenic and wild type mice.The changes of ADC were similar to the T_2 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 T_2 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.
在本文的第一部分中,我们对所获取的APPswe/PS1ΔE9双转基因小鼠进行了传代,繁殖。并通过PCR反应对小鼠的基因型进行了鉴定。应用多层面多回波SE序列和弥散加权成像(DWI)序列对4-8月龄的转基因和野生型小鼠不同脑区的T_2值和ADC值进行了测量。磁共振扫描完成后,进行老年斑和铁的组织学染色。研究发现,与野生型小鼠相比,转基因小鼠皮质和海马区的T_2值明显降低,而丘脑,胼胝体和纹状体的T_2值变化不大。ADC值的改变也与T_2值的改变相类似,转基因小鼠皮质和海马的ADC值较野生型小鼠为低,而纹状体的ADC值变化不大。组织学染色发现,4月龄及8月龄转基因小鼠的皮质及海马可出现老年斑的沉积,并且随着小鼠月龄的增加,老年斑的数目增多,面积也增大。铁染色进一步发现在转基因及野生型小鼠基底神经节处均可见到铁的沉积。铁在转基因小鼠的皮质及海马处呈棕褐色沉积,并且其分布与老年斑的分布相类似,而野生型小鼠的皮质及海马未见铁的沉积.。这些结果说明:小鼠的基因型会影响到磁共振的表型。转基因小鼠皮质和海马区的T_2值的降低可能与老年斑内的铁有关,而ADC值的降低,除了与老年斑形成引起的水分子的弥散能力减低有关之外,还与继发的神经胶质增生有关。
在本文的第二部分中,我们主要研究了AD转基因小鼠的磁共振的高分辨成像。通过对PDAPP转基因小鼠的活体扫描和APPswe/PS1ΔE9双转基因小鼠的离体扫描发现:离体扫描组织的对比度和信噪比明显较活体扫描为高,在AD转基因小鼠的活体和离体T2WI上的皮质和海马上可见一些点状的低信号区,部分的低信号区可与老年斑和铁染色相对应。这也说明了老年斑的磁共振显微成像可能有助于AD的早期诊断。
在本文的第三部分中,我们对5,8,12,16月龄的APPswe/PS1ΔE9双转基因小鼠的海马进行了活体波谱扫描,结果发现转基因小鼠海马区NAA的含量较同月龄野生型小鼠含量为低,其中16月龄的转基因小鼠海马区内NAA的水平较野生型小鼠下降更为明显。上述结果也提示1H-MRS可作为一种无创性的方法,动态的检测脑内代谢物的水平变化。
总之,一系列MRI实验以及组织学染色的结果更加深了对AD转基因小鼠表型的认识,为MRI技术在AD的发病机制和临床药物的筛选等方面提供了实验基础。
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(T_2 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 T_2-weighted multislice multiecho sequence and DWI sequence, the T_2 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 T_2 value in cortex and hippocampus of double transgenic mice was decreased compared with the wild type mice. There was no difference in the T_2 value in other brain(thalamus,corpus callosum,striatum) areas between double transgenic and wild type mice.The changes of ADC were similar to the T_2 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 T_2 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.
引文
1. Hsaio K, Borchelt DR, Olson K,et al. Age related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins.Neuron 1995 15:1203-1218.
2. Holcomb L, Gordon MN, McGowan E,et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998;4(1):97– 100.
3. Salvatore Oddo, Antonella Caccamo, Masashi Kitazawa, et.al Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiology of Aging, 2003, 24, 1063-1070.
4. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717Fβ-amyloid precursor protein.Nature 1995 373:523-527.
5. Lewis J, Mc Gowan E, Rockwood J, et al. Neurofibrillary tangles,amyotrophy and progrssive motor disturbance in mice expressing mutant(P301L)tau protein. Nat Genet 2000 25:402-405.
6. Jankowsky JL, Slunt HH, Ratovitski T, et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng, 2001, 17: 157–165.
7. Jankowsky JL, Fadale DJ, Anderson J,et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo:evidence for augmentation of a
42-specific gamma secretase. Hum Mol Genet, 2004, 13: 159–170.
8. Burgess BL, McIsaac SA, Naus KE et al. Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer's disease mouse models with abundant A beta in plasma. Neurobiol Dis, 2006, 24:114-27.
9. Garcia-Alloza M; Robbins EM; Zhang-Nunes SX; Charaterization of amyloid deposition in the APPswe/PS2dE9 mouse model of Alzheimer disease.Neurobiol Dis, 2006, 24, 516-24.
10. Garcia-Alloza M; Robbins EM; Zhang-Nunes SX; Charaterization of amyloid deposition in the APPswe/PS2dE9 mouse model of Alzheimer disease.Neurobiol Dis, 2006,24,516-24.
11. Reiserer RS; Harrison FE; Syverud DC; McDonald MP. Impaired spatial learning in the APP-PSEN1DeltaE9 bigenic mouse model of Alzheimer's disease. Genes Brain Behav 2007,6(1):54-65.
12. Virley D, Beech JS, Smart SC, et al.A temporal MRI assessment of neuropathology after transient middle cerebral artery occlusion in the rat: correlations with behavior. J Cereb Blood Flow Metab 2000, 20: 563–582.
13. Rouault TA. Iron on the brain. Nat Genet 2001, 28:299–300.
14. Gutteridge JM. Iron and oxygen radicals in brain. Ann Neurol 1992,32: 16–21.
15. House MJ, St Pierre TG, Kowdley KV, et al. Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from Alzheimer’s disease patients. Magn Reson Med 2007; 57:172–80.
16. Dexter DT, Wells FR, Agid F, et al. Increased nigral iron content in post-mortem parkinsonian brain. Lancet 1987; 41:1219–1220.
17. Inglese M, Ge Y, Jensen J, et al. Iron accumulation in the deep gray matter of patients with MS measured by magnetic field correlation. Neurology 2005,64(suppl 1):236.
18. Rottkamp CA, Raina AK, Zhu X, et al. Redox-active iron mediates amyloid-βtoxicity. Free Radical Biol Med 2001; 30:447–450.
19. Bishop GM, Robinson SR.β-Amyloid helps to protect neurons from oxidative stress. Neurobiol Aging 2000; 21(suppl 1):226.
20. Pulliam JF, Jennings CD, Kryscio RJ, et al. Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer’s disease and correlation with APOE. Am J Med Genet B Neuropsychiatr Genet 2003; 119:48–53.
21. Drayer B, Burger P, Darwin R, et al. MRI of brain iron. AJR Am J Roentgenol 1986; 147:103–110.
22. Connor JR, Menziew SL, St Martin SM, Mufson EJ. Cellular distribution of transferrin, ferritin and iron in normal and aged human brains. J Neurosci Res 1990; 27:595–611.
23. Smith MA,Harris PLR, Sayre LM,et al. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA , 1997,94:9866-9868.
24. Crapper McLachlan DR, Dalton AJ, Kruck TP, et al. Intramuscular desferrioxamine in patients with Alzheimer’s disease.Lancet 1991;337:1304–1308.
25.Matsuoka Y, Picciano M, Malester B, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol, 2001, 158:1345–1354.
26. Tsai J, Grutzendler J, Duff K,et al. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 2004,7(11): 1181–3.
27. Jack CR Jr, Garwood M, Wengenack TM, et al. In Vivo Visualization of Alzheimer’s Amyloid Plaques by Magnetic Resonance Imaging in Transgenic Mice without a Contrast Agent. Magnetic Resonance in Medicine, 2004, 52:1263–1271.
28. Sang-Pil Lee, Maria F, Falangola, et al. Visualization ofβ-Amyloid Plaques in a Transgenic Mouse Model of Alzheimer’s Disease Using MR Microscopy Without Contrast Reagents. Magnetic Resonance in Medicine, 2004, 52:538–544.
29. El Tannir El Tayara N, Delatour B, Le Cudennec C,et al. Age-related evolution of amyloid burden, iron load, and MR relaxation times in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 2006; 22(1): 199–208.
30. Laakso MP,Partanen K,Soininen H,et al. MR T2 relaxometry in Alzheimer’s disease and age-associated memory impairment. Neurobiol Aging, 1996, 17:535– 540.
31. Bondareff W,Raval J,Colletti PM,et al. Quantitative magnetic resonance imaging and the severity of dementia in Alzheimer’s disease. Am J Psychiatry, 145:853– 856.
32. Haley AP, Knight-Scott J, Fuchs KL, et al. Shortening of hippocampal spin-spin relaxation time in probable Alzheimer’s disease: a 1H magnetic resonance spectroscopy study. Neurosci Lett, 362:167–170.
33. Rouault TA. Iron on the brain. Nat Genet 2001 ,28:299–300.
34.赵喜平著磁共振成像北京:科学出版社。
35.Norris DG,Niendorf T,Leibfritz D.Health and infarcted brain tissues studied at short diffusion times: the origins of apparent restriction and the reduction in apparent diffusion coefficient. NMR Biomed 1994,7: 304–310.
36. Rudin M,Baumann D,Ekatodramis D,et al. MRI analysis of the changes in apparent water diffusion coefficient, T2 relaxation time, and cerebral blood flow and volume in the temporal evolution of cerebral infarction following permanent middle cerebral artery occlusion in rats. Exp Neurol 2001, 169:56–63.
37. van der Toorn A, Sykova E, Dijkhuizen RM, et al. Dynamic changes in water ADC, energy metabolism, extracellular space volume, and tortuosity in neonatal rat brain during global ischemia. Magn Reson Med 1996,36: 52–60.
38. Mueggler T,Meyer-LuehmannM, RauschM,et al. Restricted diffusion in the brain of transgenicmicewith cerebral amyloidosis. Eur J Neurosci 2004; 20(3): 811–817.
39. Kantarci K, Jack CR, Xu YC,et al. Mild cognitive impairment and Alzheimer disease : regional diffusivity of water.Radiology , 2001,219 (1):101-107.
40. Bozzao A, Floris R, Baviera ME,et al. Diffusion and perfusion MR imaging in cases of Alzheimer’s disease:correlations with cortical atrophy and lesion load. Am J Neuroradiol 2001, 22:1030–1036.
41. Bhagat YA, Obenaus A, Richardson J S, et al. Evolution of beta-amyloid induced neuropathology: magnetic resonance imaging and anatomical comparisons in the rodent hippocampus. MAGMA, 2002,14 (3):223-232.
42. Sun SW, Song SK, Harms MP,et al. Detection of age-dependent brain injury in a mouse model of brain amyloidosis associated with Alzheimer’s disease using magnetic resonance diffusion tensor imaging. Exp Neurol 2005; 191(1): 77–85.
1. Shoghi-Jadid K, Small GW, Agdeppa ED, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry, 2002, 10: 24–35.
2. Klunk WE, Bacskai BJ, Mathis C, et al. Imaging Aβ-plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administred Congo red derivative. J Neuropathol Exp Neurol, 2002, 61:797–805.
3. Benveniste H, Einstein G, Kim KR, et al. Detection of neuritic plaques in Alzheimer’s disease by magnetic resonance microscopy. Proc Natl Acad Sci USA , 1999, 96:14079–14084.
4. Hansen G,Crooks LE, Davis P, et al.In vivo imaging of the rat anatomy with nuclear magnetic resonance. Radiology 1980,136: 695–700.
5. Munasinghe JP,Gresham GA, Carpenter TA, et al. Magnetic resonance imaging of the normal mouse brain: comparison with histologic sections. Lab Anim Sci. 45, 674–679.
6. Aiken NR, Galey WR, Satterlee JD A peroxidative model of human erythrocyte intracellular Ca2+ changes with in vivo cell aging: measurement by 19F-NMR spectroscopy. Biochim Biophys Acta 1995,1270:52–57.
7. Benveniste H,Blackband S MR microscopy and high resolution small animal MRI: applications in neuroscience research. Prog in Neurol 2002,67:393-420.
8.赵喜平著磁共振成像北京:科学出版社.
9. Back PJ, Coy A, Xia Y,et al. Some biophysical applications of motional contrast in n.m.r. microscopy. Int J Biol Macromol. 1991,13:181–189.
10. Callaghan PT, Clark CJ, Forde LC. Use of static and dynamic NMR microscopy to investigate the origins of contrast in images of biological tissues. Biophys. Chem. 1994,50:225–235.
11. Werner M, Chott A, Fabiano A,et al. Effect of formalin tissue fixation and processingon immunohistochemistry. Am J Surg Pathol. 2000,24:1016–1019.
12. Tovi M,Ericsson A. Measurements of T1 and T2 over time in formalin-fixed human whole-brain specimens. Acta Radiologica. 1992,33 (5):400–402.
13. Pattany PM, Puckett WR, Klose KJ, et al. High-resolution diffusion-weighted MR of fresh and fixed cat spinal cords: evaluation of diffusion coefficients and anisotropy. AJNR Am. J. Neuroradiol. 1997,18:1049–1056.
14. Johnson GA, Cofer GP, Gewalt SL,et al. Morphologic phenotyping with MR microscopy: the visible mouse. Radiology, 2002:222: 789–793.
15. Benveniste H, Kim K,Zhang L,et al. Magnetic resonance microscopy of the C57BL mouse brain. NeuroImage 2000,11:601–611.
16. Smith BR, Johnson GA, Groman EV, et al. Magnetic resonance microscopy of mouse embryos. Proc. Natl. Acad. Sci. U.S.A. 1994,91:3530–3533.
17. Benveniste H, Qui H., Hedlund, LW, et al. Spinal cord neural anatomy in rats examined by in vivo magnetic resonance microscopy. Reg. Anesth. Pain Med.1998, 23, 589–599.
18. Jiang Q, Choop M, Zhang ZG, et al. The effect of hypothermia on transient focal ischemia in rat brain evaluated by diffusion- and perfusion-weighted NMR imaging. J Cereb Blood Flow Metab. 1994,14:732–741.
19. Hedlund LW, Cofer GP, Owen SJ,et al. MR-compatible ventilator for small animals: computer-controlled ventilation for proton and noble gas imaging. Magn. Reson. Imaging 2000,18:753–759.
20. Matsuoka Y, Picciano M, Malester B, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 2001,158:1345–1354.
21. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992,256: 184–185.
22.Lovell MA, Robertson JD,Teesdale WJ,et al. Copper, iron and zinc in Alzheimer’s disease senile plaques. J neuro sci 1998,158:47-52.
23. Dhenain M, Privat N, Duyckaerts C, et al. Senile plaques do not induce susceptibilityeffects in T2*- weighted MR microscopic images. NMR Biomed , 2002, 15:197–203.
24. Helpern JA, Lee S-P, Falangola MF, et al.MRI assessment of neuropathology in a transgenic mouse model of Alzheimer’s disease. Magn Reson Med , 2004,51:794–798.
25. Zhang J, Yarowsky P, Gordon MN,et al. Detection of amyloid plaques in mouse models of Alzheimer’sdisease by magnetic resonance imaging. Magn Reson Med, 2004,51:452–457.
26. Jack CR Jr, Garwood M, Wengenack TM, et al. In Vivo Visualization of Alzheimer’s Amyloid Plaques by Magnetic Resonance Imaging in Transgenic Mice without a Contrast Agent. Magnetic Resonance in Medicine, 2004, 52:1263–1271.
27. Sang-Pil Lee, Maria F, Falangola, et al. Visualization ofβ-Amyloid Plaques in a Transgenic Mouse Model of Alzheimer’s Disease Using MR Microscopy Without Contrast Reagents. Magnetic Resonance in Medicine, 2004, 52:538–544.
28. Vanhoutte G, Dewachter I, Borghgraef P,et al. Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer’s disease. Magn Reson Med 2005; 53(3): 607–613.
29. Jack CR Jr, Wengenack TM, Reyes DA,et al. In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer’s transgenic mice. J Neurosci 2005; 25(43): 10041–10048.
30. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing the V717Fβ-amyloid precursor protein. Nature , 1995, 373:523-527.
31.秦川,朱华,张兵林,等.阿尔茨海默症转基因动物模型脑组织病理学及免疫组化研究.中国实验动物学报,2000,8(4):213-217.
32. Connor JR, Menzies SL, St Martin SM, et al. A histochemical study of iron, transferrin, and ferritin in Alzheimer’s diseased brains.J Neurosci Res , 1992,31:75–83.
33. Bartzokis G, Sultzer D, Cummings J, et al. In vivo evaluation of brani iron in Alzheimer disease using magnetic resonance imaging. Ar Gen Psychiatry, 2000, 57:47- 53.
34. Richardson DR. Novel chelators for central nervous system disorders that involve alterations in themetabolism of iron and other metal ions. Ann NY Acad Sci,2004,1012:326–341.
35. Poduslo JF, Wengenack TM, Curran GL, et al. Molecular targeting of Alzheimer’s amyloid plaques for contrast-enhanced magnetic resonance imaging. Neurobiol Dis, 2002,11:315–329.
36. Wadghiri YZ, Sigurdsson EM, Sadowski M, et al. Detection of Alzheimer’s amyloid in transgenic mice using magnetic resonance microimaging. Magn Reson Med ,2003,50:293–302.
37. Higuchi M, Iwata N, Matsuba Y,et al. 19F and 1H MRI detection of amyloid beta plaques in vivo. Nat Neurosci 2005; 8(4): 527–533.
38.Borthakur A, Gur T, Wheaton AJ,et al. In vivo measurement of plaque burden in a mouse model of Alzheimer's disease. J Magn Reson Imaging 2006 ,24(5):1011-7.
39. Faber C, Zahneisen B, Tippmann F,et al. Gradient-echo and CRAZED imaging for minute detection of Alzheimer plaques in an APPV717I x ADAM10-dn mouse model. Magn Reson Med. 2007 ,57(4):696-703.
40. Nakada Tsutomu, Matsuzawa Hitoshi,Igarashi Hironaka et al. In Vivo Visualization of Senile-Plaque-Like Pathology in Alzheimer's Disease Patients by MR Microscopy on a 7T System. J Neuroimaging. 2008 ,18(2):125-9.
1.Boska MD, Lewis TB, Destache CJ,et al. Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson’s disease.J Neurosci 2005; 25: 1691–1700.
2. Koga K, Mori A, Ohashi S,et al. H MRS identifies lactate rise in the striatum of MPTP-treated C57BL/6 mice. Eur J Neurosci 2006; 23: 1077–1081.
3. Brownell AL, Jenkins BG, Elmaleh DR,et al. Combined PET/MRS brain studies show dynamicand long-term physiological changes in a primate model of Parkinson disease. Nat Med 1998; 4: 1308–1312.
4. van Dellen A, Welch J, Dixon RM,et al. N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington’s disease mice. Neuroreport 2000; 11: 3751–3757.
5. Tsang TM,Woodman B, McLoughlin GA,et al. Metabolic characterization of the R6/2 transgenic mouse model of Huntington’s disease by highresolution MAS 1H NMR spectroscopy. J Proteome Res 2006; 5: 483–492.
6. Jenkins BG, Klivenyi P, Kustermann E,et al. Nonlinear decrease over time in N-acetylaspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington’s disease mice. J Neurochem 2000; 74: 2108–2119.
7. Andreassen OA, Jenkins BG, Dedeoglu A,et al. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation.J Neurochem 2001; 77: 383–390.
8. Choi JK,Jenkins BG, et al. Application of MRS to mouse models of neurodegenerative illness NMR Biomed 2007; 20: 216–237.
9 . Simmons ML, Frondoza CG, Coyle JT. Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 1991; 45: 37–45.
10. Urenjak J, Williams SR, Gadian DG,et al. Specific expression of N-acetylaspartate in neurons, oligodendrocyte- type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 1992; 59: 55–61.
11. Urenjak J, Williams SR, Gadian DG,et al. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993; 13: 981–989.
12.Burgess BL, McIsaac SA,Naus KE et al . Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer's disease mouse models with abundant A beta in plasma. Neurobiol Dis,2006,24:114-27.
13.Dedeoglu A, Choi JK, Cormier K, et al.Magnetic resonance spectroscopic analysis of Alzheimer's disease mouse brain that express mutant human APP shows altered neurochemical profile. Brain Res 2004;1012:60-65.
14.Marjanska M, Curran GL, Wengenack TM,et al. Monitoring disease progression in transgenic mouse models of Alzheimer's disease with proton magnetic resonance spectroscopy. Proc Natl Acad Sci U. S. A. 2005;102: 11906-11910.
15.von Kienlin M, Kunnecke B, Metzger F , et al.Altered metabolic profile in the frontal cortex of PS2APP transgenic mice, monitored throughout their life span. Neurobiol Dis 2005;18:32-39.
16.Oberg J,Spenger C, Wang FH,et al. Age related changes in brain metabolites observed by 1H MRS in APP/PS1 mice. Neurobiol Aging 2007.
17. Krishnan KR, Charles HC, Doraiswamy PM, et al. Randomized, placebocontrolled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease.Am. J. Psychiatry ,2003,160:2003–2011.
18.Ross BD, Hoang TQ, Bluml S,et al. In vivo magnetic resonance spectroscopy of human fetal neural transplants. NMR Biomed 1999; 12: 221–236.
19. Clifford R. Jack, Jr, Malgorzata Marjanska, Thomas M. Wengenack, et al. Magnetic Resonance Imaging of Alzheimer's Pathology in the Brains of Living Transgenic Mice: ANew Tool in Alzheimer's Disease Research. The Neuroscientist,2007,13:38-48 .
20. Constans JM, Meyerhoff DJ, Gerson J, et al. 1H MR spectroscopic imaging of white matter signal hyperintensities:Alzheimer disease and ischemic vascular dementia. Radiology 1995;197:517-523.
21. MacKay S, Ezekiel F, Di Sclafani V, et al. Alzheimer disease and subcortical ischemic vascular dementia:evaluation by combining MR imaging segmentation and H-1 MR spectroscopic imaging. Radiology 1996;198:537-545.
22. Kizu O, Yamada K, Ito H, et al. Posterior cingulate metabolic changes in frontotemporal lobar degeneration detected by magnetic resonance spectroscopy. Neuroradiology 2004;46:277-281.
23. Frederick BD, Lyoo IK, Satlin A, et al. In vivo proton magnetic resonance spectroscopy of the temporal lobe in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:1313-1322.
24. Kantarci K, Petersen RC, Boeve BF, et al. 1H MR spectroscopy in common dementias. Neurology 2004;63:1393-1398.
25. Chantal S, Braun CM, Bouchard RW, et al. Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial temporal lobes of patients with mild cognitive impairment and Alzheimer disease. Brain Res 2004;1003:26-35.
26.Satlin A, Bodick N, Offen WW, et al. Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer’s disease: changes after treatment with xanomeline,an M1 selective cholinergic agonist. Am J Psychiatry 1997;154:1459-1461.
1.Wimo A ,Winblad B,Aguero-Torres H , et al. The magnitude of dementia occurrence in the world . Alzheimer Dis Assoc Disord 2003 , 17 (2) : 632-67.
2.洪震.我国阿尔茨海默病的研究现状及展望.中华神经科杂志, 2001 , 34 (4) :193-195.
3.赵喜平著磁共振成像北京:科学出版社
4 . Simmons ML, Frondoza CG, Coyle JT. Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 1991; 45: 37–45.
5. Urenjak J, Williams SR, Gadian DG,et al. Specific expression of N-acetylaspartate in neurons, oligodendrocyte- type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 1992; 59: 55–61.
6. Urenjak J, Williams SR, Gadian DG,et al. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993; 13: 981–989.
7. Shonk TK, Moats RA, Gifford P,et al. Probable Alzheimer disease: diagnosis with proton MR spectroscopy . Radiology 1995; 195: 65–72.
8. Dunlop DS, Mc Hale DM, Lajtha A. Decreased brain N-acetylaspartate in Huntington’s disease. Brain Res 1992; 580: 44–48.
9. Mathews PM, Andermann F, Silver K, et al. Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyo- pathies.Neurology 1993; 43: 2484–2490.
10. Fenstermacher MJ, Narayana PA. Serial proton magnetic resonance spectroscopy of ischemic brain injury in humans. Invest Radiol 1990; 25: 1034–1039.
11. Higuchi T, Fernandez EJ, Maudsley AA,et al. Mapping of lactate and N-acetyl-L-aspartate predicts infarction during acute focal ischemia: in vivo1H magnetic resonance spectroscopy in rats. Neurosurgery 1996; 38: 121–129.
12. Birken DL, Oldendorf WH. N-Acetyl-L-aspartic acid: a literature review of a compound prominent in 1H-NMR spectroscopic studies of brain. Neurosci. Biobehav Rev. 1989; 13: 23–31.
13. Taylor DL, Davies SE, Obrenovitch TP,et al. Investigation into the role of N-acetylaspartate in cerebral osmoregulation. J Neurochem 1995; 65: 275–281.
14. Baslow MH. Evidence supporting a role for N-acetyl-L-aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytical review. Neurochem Int 2002; 40:295–300.
15. Baslow MH. Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation. J Mol Neurosci 2003; 21: 185–190.
16. Choi IY, Gruetter R. Dynamic or inert metabolism ? Turnover of N-acetyl aspartate and glutathione from D-[1-13C]glucose in the rat brain in vivo. J Neurochem 2004; 91: 778–787.
17. Podo F. Tumour phospholipid metabolism. NMR Biomed 1999;12: 413–439.
18. Mason GF, Pan JW, Ponder SL,et al. Detection of brain glutamate and glutamine in spectroscopic images at 4.1 T. Magn Reson Med 1994; 32: 142–145.
19. Bristol LA, Rothstein JD. Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Ann Neurol 1996; 39: 676–679.
20. Rothstein JD, Van Kammen M, Levey AI,et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995; 38: 73–84.
21. Andreassen OA, Jenkins BG, Dedeoglu A,et al. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem 2001; 77: 383–390.
22. Jenkins BG, Klivenyi P, Kustermann E,et al. Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington’s disease mice. J Neurochem 2000; 74: 2108–2119.
23. Prichard J, Rothman D, Novotny E,et al. Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci USA 1991; 88: 5829–5831.
24. Petroff OA, Graham GD, Blamire AM,et al. Spectroscopic imaging of stroke in humans: histopathology correlates of spectral changes. Neurology 1992; 42: 1349–1354.
25. Dager SR, Strauss WL, Marro KI,et al. Proton magnetic resonance spectroscopy investigation of hyperventilation in subjects with panic disorder and comparison subjects. Am J Psychiatry 1995; 152: 666–672.
26. Brand A, Richter-Landsberg C, Leibfritz D. Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 1993; 15: 289–298.
27.Thurston JH, Sherman WR, Hauhart RE, et al. myo-inositol: a newly identified nonnitrogenous osmoregulatory molecule in mammalian brain. Pediatr Res 1989; 26: 482–485.
28. Isaacks RE, Bender AS, Kim CY,et al. Effect of ammonia and methionine sulfoximine on myo-inositol transport in cultured astrocytes. Neurochem Res 1999; 24: 51–59.
29.M.B. Burg, E.D. Kwon, D. Kultz, Regulation of gene expression by hypertonicity.Annu Rev Physiol 1997;59:437–455.
30.Games D,Adams D,Alessandrini R,et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717Fβ-amyloid precursor protein.Nature 19953;73:523-527。
31.Hsaio K,Borchelt DR,Olson K,et al. Age related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins.Neuron 1995;15:1203-1218.
32.. Sturchler-Pierrat C,Abramowski D,Duke M,et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997;94:13287-13292
33. Sturchler-Pierrat C,Abramowski D,Duke M,et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA1997;94:13287-13292.
34. Duff K,Eckman C,Zehr C,et al.Increased amyloid-β42(43) in brains of mice experessing mutant presenilin 1. Nature 1996;383:710-713.
35. Holcomb L, Gordon MN, McGowan E,et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998;4(1):97– 100.
36. Herzig M.C, et al. Aβis targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 2004 :7954–960.
37. McGowan E. et al. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 2005;47:191–199.
38. Lewis J,Mc Gowan E,Rockwood J,et al. Neurofibrillary tangles,amyotrophy and progrssive motor disturbance in mice expressing mutant(P301L)tau protein. Nat Genet 2000;25:402-405.
39.Allen B,et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 2002;22:9340–9351.
40. Tanemura K,et al.Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol Dis 2001 8:1036–1045.
41. Tatebayashi Y, et al. Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad. Sci 2002;99:13896–13901.
42. SantaCruz K,et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481.
43. Andorfer C,et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 2003;86:582–590.
44. Lewis J,Dickson DW,Lin W-L,et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001;293:1487-1491.
45.Salvatore Oddo,Antonella Caccamo,Masashi Kitazawa,et al Amyloid depositionprecedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiology of Aging,2003;24:1063-1070.
46.Dedeoglu A, Choi JK, Cormier K, et al.Magnetic resonance spectroscopic analysis of Alzheimer's disease mouse brain that express mutant human APP shows altered neurochemical profile. Brain Res 2004;1012:60-65.
47.Marjanska M, Curran GL, Wengenack TM,et al. Monitoring disease progression in transgenic mouse models of Alzheimer's disease with proton magnetic resonance spectroscopy. Proc Natl Acad Sci U. S. A. 2005;102: 11906-11910.
48.von Kienlin M, Kunnecke B, Metzger F , et al.Altered metabolic profile in the frontal cortex of PS2APP transgenic mice, monitored throughout their life span. Neurobiol Dis 2005;18:32-39.
49.Oberg J,Spenger C, Wang FH,et al. Age related changes in brain metabolites observed by 1H MRS in APP/PS1 mice. Neurobiol Aging 2007.
50.Choi JK,Jenkins BG, et al. Application of MRS to mouse models of neurodegenerative illness NMR Biomed 2007; 20: 216–237.
51.Doraiswamy M, Charles C, Krishnan R,et al.Prediction of cognitive decline in early Alzheimer’s disease. Lancet 1998;352:1678.
52.Parnetti L, Tarducci R, Presciutti O, et al. Proton magnetic resonance spectroscopy can differentiate Alzheimer’s disease from normal aging. Mech Ageing Dev 1997;97:9-14.
53.Schuff N, Capizzano AA, Du AT, et al. Selective reduction of N-acetylaspartate in medial temporal and parietal lobes in AD. Neurology 2002;58:928-935.
54.Kantarci K, Petersen RC, Boeve BF, et al. 1H MR spectroscopy in common dementias. Neurology 2004;63:1393-1398.
55 . Kizu O, Yamada K, Ito H, et al. Posterior cingulate metabolic changes in frontotemporal lobar degeneration detected by magnetic resonance spectroscopy. Neuroradiology 2004;46:277-281.
56.Moats RA, Ernst T, Shonk TK, et al. Abnormal cerebral metabolite concentrations in patients with probable Alzheimer disease. Magn Reson Med 1994; 32:110-115.
57.Frederick BD, Lyoo IK, Satlin A, et al. In vivo proton magnetic resonance spectroscopy of the temporal lobe in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:1313-1322.
58.Rai G, McConnell J, Waldman A, et al. Brain proton spectroscopy in dementia: an aid to clinical diagnosis. Lancet 1999;353:1063-1064.
59.Chantal S, Braun CM, Bouchard RW, et al. Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial temporal lobes of patients with mild cognitive impairment and Alzheimer disease. Brain Res 2004;1003:26-35.
60.Ackl N, Ising M, Schreiber YA, et al. Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 2005;384: 23-28.
61.Miller B, Moats R, Shonk T, et al. Alzheimer disease depiction of increased cerebral myoinositol with proton MR spectroscopy. Radiology 1993;187:433-437.
62.Parnetti L, Lowenthal DT, Presciutti O, et al. 1H-MRS,MRI-based hippocampal volumetry, and 99mTc-HMPAO-SPECT in normal aging, age-associated memory impairment, and probable Alzheimer’s disease.J Am Geriatr Soc 1996;44:133-138.
63. Jessen F, Block W, Traber F, et al. Proton MR spectroscopy detects a relative decrease of N-acetylaspartate in the medial temporal lobe of patients with AD. Neurology 2000;55:684-688.
64. Ernst T, Chang L, Melchor R, et al. Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe 1H MR spectroscopy. Radiology 1997;203:829-836.
65.Huang W, Alexander GE, Chang L, et al. Brain metabolite concentration and dementia severity in Alzheimer’s disease: a 1H MRS study. Neurology 2001;57:626-632.
66.Kantarci K, Jack Jr CR, Xu YC, et al. Regional metabolic patterns in mild cognitive impairment and Alzheimer’s disease: a 1H MRS study. Neurology 2000;55:210-217.
67. Shonk T, Moats R, Gifford P, et al. Probable Alzheimer disease: diagnosis with proton MR spectroscopy. Radiology 1995;195:65-72.
68. Constans JM, Meyerhoff DJ, Gerson J, et al. 1H MR spectroscopic imaging of white matter signal hyperintensities:Alzheimer disease and ischemic vascular dementia. Radiology 1995;197:517-523.
69. MacKay S, Ezekiel F, Di Sclafani V, et al. Alzheimer disease and subcortical ischemic vascular dementia:evaluation by combining MR imaging segmentation and H-1 MR spectroscopic imaging. Radiology 1996;198:537-545.
70. Meyerhoff D, MacKay S, Constans J, et al. Axonal injury and membrane alterations in Alzheimer’s disease suggested by in vivo proton magnetic resonance spectroscopic imaging. Ann Neurol 1994;36:40-47.
71. Pfefferbaum A, Adalsteinsson E, Spielman D, et al.In vivo brain concentration of N-acetyl compounds,creatine, and choline in Alzheimer’s disease. Arch Gen Psychiatry 1999;56:185-192.
72. Christensen P, Schlosser A, Henriksen O. Reduced N-acetylaspartate content in the frontal part of the brain in patients with probable Alzheimer’s disease. Magn Reson Imaging 1995;13:457-462.
73. Kantarci K, Jack Jr CR. Neuroimaging in Alzheimer disease: an evidence-based review. Neuroimaging Clin N Am 2003;13:197-209.
74. Rose SE, de Zubicaray GI, Wang D, et al. A 1H MRS study of probable Alzheimer’s disease and normal aging: implications for longitudinal monitoring of dementia progression. Magn Reson Imaging 1999;17:291-299.
75. Schuff N, Amend D, Ezekiel F, et al. Changes of hippocampal N-acetyl aspartate and volume in Alzheimer’s disease. A proton MR spectroscopic imaging and MRI study. Neurology 1997;49:1513-1521.
76. Bottomley P, Cousins J, Pendrey D, et al. Alzheimer dementia: quantification of energy metabolism and mobile phosphoesters with P-31 NMR spectroscopy. Radiology1992;183:695-699.
77.Burri R, Bigler P, Straehl P, et al. Brain development: 1H magnetic resonance spectroscopy of rat brain extracts compared with chromatographic methods. Neurochem Res 1990;15:1009-1016.
78. Satlin A, Bodick N, Offen WW, et al. Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer’s disease: changes after treatment with xanomeline,an M1 selective cholinergic agonist. Am J Psychiatry 1997;154:1459-1461.
79. Klunk WE, Xu C, Panchalingham K, McClure RJ, Pettegrew JW Quantitative 1H and 31P MRS of PCA extracts of postmortem Alzheimer_s disease brain. Neurobiol Aging 1996;17:349-357
80. Modrego PJ, Fayed N, Pina MA Conversion from mild cognitive impairment to probably Alzheimer_s disease predicted by brain magnetic resonance spectroscopy. Am J Psychiatry 2005;162: 667-675
81. Falini A, Bozzali M, Magnani G, et al. A whole brain MR spectroscopy study from patients with Alzheimer_s disease and mild cognitive impairment. Neuroimage 2005;26:1159-1163.
82.Krishnan KR, Charles HC, Doraiswamy PM, et al. Randomized, placebocontrolled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease.Am. J. Psychiatry ,2003,160:2003–2011.
83.Ross BD, Hoang TQ, Bluml S,et al. In vivo magnetic resonance spectroscopy of human fetal neural transplants. NMR Biomed 1999; 12: 221–236.
84. Clifford R. Jack, Jr, Malgorzata Marjanska, Thomas M. Wengenack, et al. Magnetic Resonance Imaging of Alzheimer's Pathology in the Brains of Living Transgenic Mice: A New Tool in Alzheimer's Disease Research. The Neuroscientist,2007,13:38-48
2. Holcomb L, Gordon MN, McGowan E,et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998;4(1):97– 100.
3. Salvatore Oddo, Antonella Caccamo, Masashi Kitazawa, et.al Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiology of Aging, 2003, 24, 1063-1070.
4. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717Fβ-amyloid precursor protein.Nature 1995 373:523-527.
5. Lewis J, Mc Gowan E, Rockwood J, et al. Neurofibrillary tangles,amyotrophy and progrssive motor disturbance in mice expressing mutant(P301L)tau protein. Nat Genet 2000 25:402-405.
6. Jankowsky JL, Slunt HH, Ratovitski T, et al. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng, 2001, 17: 157–165.
7. Jankowsky JL, Fadale DJ, Anderson J,et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo:evidence for augmentation of a
42-specific gamma secretase. Hum Mol Genet, 2004, 13: 159–170.
8. Burgess BL, McIsaac SA, Naus KE et al. Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer's disease mouse models with abundant A beta in plasma. Neurobiol Dis, 2006, 24:114-27.
9. Garcia-Alloza M; Robbins EM; Zhang-Nunes SX; Charaterization of amyloid deposition in the APPswe/PS2dE9 mouse model of Alzheimer disease.Neurobiol Dis, 2006, 24, 516-24.
10. Garcia-Alloza M; Robbins EM; Zhang-Nunes SX; Charaterization of amyloid deposition in the APPswe/PS2dE9 mouse model of Alzheimer disease.Neurobiol Dis, 2006,24,516-24.
11. Reiserer RS; Harrison FE; Syverud DC; McDonald MP. Impaired spatial learning in the APP-PSEN1DeltaE9 bigenic mouse model of Alzheimer's disease. Genes Brain Behav 2007,6(1):54-65.
12. Virley D, Beech JS, Smart SC, et al.A temporal MRI assessment of neuropathology after transient middle cerebral artery occlusion in the rat: correlations with behavior. J Cereb Blood Flow Metab 2000, 20: 563–582.
13. Rouault TA. Iron on the brain. Nat Genet 2001, 28:299–300.
14. Gutteridge JM. Iron and oxygen radicals in brain. Ann Neurol 1992,32: 16–21.
15. House MJ, St Pierre TG, Kowdley KV, et al. Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from Alzheimer’s disease patients. Magn Reson Med 2007; 57:172–80.
16. Dexter DT, Wells FR, Agid F, et al. Increased nigral iron content in post-mortem parkinsonian brain. Lancet 1987; 41:1219–1220.
17. Inglese M, Ge Y, Jensen J, et al. Iron accumulation in the deep gray matter of patients with MS measured by magnetic field correlation. Neurology 2005,64(suppl 1):236.
18. Rottkamp CA, Raina AK, Zhu X, et al. Redox-active iron mediates amyloid-βtoxicity. Free Radical Biol Med 2001; 30:447–450.
19. Bishop GM, Robinson SR.β-Amyloid helps to protect neurons from oxidative stress. Neurobiol Aging 2000; 21(suppl 1):226.
20. Pulliam JF, Jennings CD, Kryscio RJ, et al. Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer’s disease and correlation with APOE. Am J Med Genet B Neuropsychiatr Genet 2003; 119:48–53.
21. Drayer B, Burger P, Darwin R, et al. MRI of brain iron. AJR Am J Roentgenol 1986; 147:103–110.
22. Connor JR, Menziew SL, St Martin SM, Mufson EJ. Cellular distribution of transferrin, ferritin and iron in normal and aged human brains. J Neurosci Res 1990; 27:595–611.
23. Smith MA,Harris PLR, Sayre LM,et al. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA , 1997,94:9866-9868.
24. Crapper McLachlan DR, Dalton AJ, Kruck TP, et al. Intramuscular desferrioxamine in patients with Alzheimer’s disease.Lancet 1991;337:1304–1308.
25.Matsuoka Y, Picciano M, Malester B, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol, 2001, 158:1345–1354.
26. Tsai J, Grutzendler J, Duff K,et al. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 2004,7(11): 1181–3.
27. Jack CR Jr, Garwood M, Wengenack TM, et al. In Vivo Visualization of Alzheimer’s Amyloid Plaques by Magnetic Resonance Imaging in Transgenic Mice without a Contrast Agent. Magnetic Resonance in Medicine, 2004, 52:1263–1271.
28. Sang-Pil Lee, Maria F, Falangola, et al. Visualization ofβ-Amyloid Plaques in a Transgenic Mouse Model of Alzheimer’s Disease Using MR Microscopy Without Contrast Reagents. Magnetic Resonance in Medicine, 2004, 52:538–544.
29. El Tannir El Tayara N, Delatour B, Le Cudennec C,et al. Age-related evolution of amyloid burden, iron load, and MR relaxation times in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 2006; 22(1): 199–208.
30. Laakso MP,Partanen K,Soininen H,et al. MR T2 relaxometry in Alzheimer’s disease and age-associated memory impairment. Neurobiol Aging, 1996, 17:535– 540.
31. Bondareff W,Raval J,Colletti PM,et al. Quantitative magnetic resonance imaging and the severity of dementia in Alzheimer’s disease. Am J Psychiatry, 145:853– 856.
32. Haley AP, Knight-Scott J, Fuchs KL, et al. Shortening of hippocampal spin-spin relaxation time in probable Alzheimer’s disease: a 1H magnetic resonance spectroscopy study. Neurosci Lett, 362:167–170.
33. Rouault TA. Iron on the brain. Nat Genet 2001 ,28:299–300.
34.赵喜平著磁共振成像北京:科学出版社。
35.Norris DG,Niendorf T,Leibfritz D.Health and infarcted brain tissues studied at short diffusion times: the origins of apparent restriction and the reduction in apparent diffusion coefficient. NMR Biomed 1994,7: 304–310.
36. Rudin M,Baumann D,Ekatodramis D,et al. MRI analysis of the changes in apparent water diffusion coefficient, T2 relaxation time, and cerebral blood flow and volume in the temporal evolution of cerebral infarction following permanent middle cerebral artery occlusion in rats. Exp Neurol 2001, 169:56–63.
37. van der Toorn A, Sykova E, Dijkhuizen RM, et al. Dynamic changes in water ADC, energy metabolism, extracellular space volume, and tortuosity in neonatal rat brain during global ischemia. Magn Reson Med 1996,36: 52–60.
38. Mueggler T,Meyer-LuehmannM, RauschM,et al. Restricted diffusion in the brain of transgenicmicewith cerebral amyloidosis. Eur J Neurosci 2004; 20(3): 811–817.
39. Kantarci K, Jack CR, Xu YC,et al. Mild cognitive impairment and Alzheimer disease : regional diffusivity of water.Radiology , 2001,219 (1):101-107.
40. Bozzao A, Floris R, Baviera ME,et al. Diffusion and perfusion MR imaging in cases of Alzheimer’s disease:correlations with cortical atrophy and lesion load. Am J Neuroradiol 2001, 22:1030–1036.
41. Bhagat YA, Obenaus A, Richardson J S, et al. Evolution of beta-amyloid induced neuropathology: magnetic resonance imaging and anatomical comparisons in the rodent hippocampus. MAGMA, 2002,14 (3):223-232.
42. Sun SW, Song SK, Harms MP,et al. Detection of age-dependent brain injury in a mouse model of brain amyloidosis associated with Alzheimer’s disease using magnetic resonance diffusion tensor imaging. Exp Neurol 2005; 191(1): 77–85.
1. Shoghi-Jadid K, Small GW, Agdeppa ED, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry, 2002, 10: 24–35.
2. Klunk WE, Bacskai BJ, Mathis C, et al. Imaging Aβ-plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administred Congo red derivative. J Neuropathol Exp Neurol, 2002, 61:797–805.
3. Benveniste H, Einstein G, Kim KR, et al. Detection of neuritic plaques in Alzheimer’s disease by magnetic resonance microscopy. Proc Natl Acad Sci USA , 1999, 96:14079–14084.
4. Hansen G,Crooks LE, Davis P, et al.In vivo imaging of the rat anatomy with nuclear magnetic resonance. Radiology 1980,136: 695–700.
5. Munasinghe JP,Gresham GA, Carpenter TA, et al. Magnetic resonance imaging of the normal mouse brain: comparison with histologic sections. Lab Anim Sci. 45, 674–679.
6. Aiken NR, Galey WR, Satterlee JD A peroxidative model of human erythrocyte intracellular Ca2+ changes with in vivo cell aging: measurement by 19F-NMR spectroscopy. Biochim Biophys Acta 1995,1270:52–57.
7. Benveniste H,Blackband S MR microscopy and high resolution small animal MRI: applications in neuroscience research. Prog in Neurol 2002,67:393-420.
8.赵喜平著磁共振成像北京:科学出版社.
9. Back PJ, Coy A, Xia Y,et al. Some biophysical applications of motional contrast in n.m.r. microscopy. Int J Biol Macromol. 1991,13:181–189.
10. Callaghan PT, Clark CJ, Forde LC. Use of static and dynamic NMR microscopy to investigate the origins of contrast in images of biological tissues. Biophys. Chem. 1994,50:225–235.
11. Werner M, Chott A, Fabiano A,et al. Effect of formalin tissue fixation and processingon immunohistochemistry. Am J Surg Pathol. 2000,24:1016–1019.
12. Tovi M,Ericsson A. Measurements of T1 and T2 over time in formalin-fixed human whole-brain specimens. Acta Radiologica. 1992,33 (5):400–402.
13. Pattany PM, Puckett WR, Klose KJ, et al. High-resolution diffusion-weighted MR of fresh and fixed cat spinal cords: evaluation of diffusion coefficients and anisotropy. AJNR Am. J. Neuroradiol. 1997,18:1049–1056.
14. Johnson GA, Cofer GP, Gewalt SL,et al. Morphologic phenotyping with MR microscopy: the visible mouse. Radiology, 2002:222: 789–793.
15. Benveniste H, Kim K,Zhang L,et al. Magnetic resonance microscopy of the C57BL mouse brain. NeuroImage 2000,11:601–611.
16. Smith BR, Johnson GA, Groman EV, et al. Magnetic resonance microscopy of mouse embryos. Proc. Natl. Acad. Sci. U.S.A. 1994,91:3530–3533.
17. Benveniste H, Qui H., Hedlund, LW, et al. Spinal cord neural anatomy in rats examined by in vivo magnetic resonance microscopy. Reg. Anesth. Pain Med.1998, 23, 589–599.
18. Jiang Q, Choop M, Zhang ZG, et al. The effect of hypothermia on transient focal ischemia in rat brain evaluated by diffusion- and perfusion-weighted NMR imaging. J Cereb Blood Flow Metab. 1994,14:732–741.
19. Hedlund LW, Cofer GP, Owen SJ,et al. MR-compatible ventilator for small animals: computer-controlled ventilation for proton and noble gas imaging. Magn. Reson. Imaging 2000,18:753–759.
20. Matsuoka Y, Picciano M, Malester B, et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 2001,158:1345–1354.
21. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992,256: 184–185.
22.Lovell MA, Robertson JD,Teesdale WJ,et al. Copper, iron and zinc in Alzheimer’s disease senile plaques. J neuro sci 1998,158:47-52.
23. Dhenain M, Privat N, Duyckaerts C, et al. Senile plaques do not induce susceptibilityeffects in T2*- weighted MR microscopic images. NMR Biomed , 2002, 15:197–203.
24. Helpern JA, Lee S-P, Falangola MF, et al.MRI assessment of neuropathology in a transgenic mouse model of Alzheimer’s disease. Magn Reson Med , 2004,51:794–798.
25. Zhang J, Yarowsky P, Gordon MN,et al. Detection of amyloid plaques in mouse models of Alzheimer’sdisease by magnetic resonance imaging. Magn Reson Med, 2004,51:452–457.
26. Jack CR Jr, Garwood M, Wengenack TM, et al. In Vivo Visualization of Alzheimer’s Amyloid Plaques by Magnetic Resonance Imaging in Transgenic Mice without a Contrast Agent. Magnetic Resonance in Medicine, 2004, 52:1263–1271.
27. Sang-Pil Lee, Maria F, Falangola, et al. Visualization ofβ-Amyloid Plaques in a Transgenic Mouse Model of Alzheimer’s Disease Using MR Microscopy Without Contrast Reagents. Magnetic Resonance in Medicine, 2004, 52:538–544.
28. Vanhoutte G, Dewachter I, Borghgraef P,et al. Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer’s disease. Magn Reson Med 2005; 53(3): 607–613.
29. Jack CR Jr, Wengenack TM, Reyes DA,et al. In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer’s transgenic mice. J Neurosci 2005; 25(43): 10041–10048.
30. Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing the V717Fβ-amyloid precursor protein. Nature , 1995, 373:523-527.
31.秦川,朱华,张兵林,等.阿尔茨海默症转基因动物模型脑组织病理学及免疫组化研究.中国实验动物学报,2000,8(4):213-217.
32. Connor JR, Menzies SL, St Martin SM, et al. A histochemical study of iron, transferrin, and ferritin in Alzheimer’s diseased brains.J Neurosci Res , 1992,31:75–83.
33. Bartzokis G, Sultzer D, Cummings J, et al. In vivo evaluation of brani iron in Alzheimer disease using magnetic resonance imaging. Ar Gen Psychiatry, 2000, 57:47- 53.
34. Richardson DR. Novel chelators for central nervous system disorders that involve alterations in themetabolism of iron and other metal ions. Ann NY Acad Sci,2004,1012:326–341.
35. Poduslo JF, Wengenack TM, Curran GL, et al. Molecular targeting of Alzheimer’s amyloid plaques for contrast-enhanced magnetic resonance imaging. Neurobiol Dis, 2002,11:315–329.
36. Wadghiri YZ, Sigurdsson EM, Sadowski M, et al. Detection of Alzheimer’s amyloid in transgenic mice using magnetic resonance microimaging. Magn Reson Med ,2003,50:293–302.
37. Higuchi M, Iwata N, Matsuba Y,et al. 19F and 1H MRI detection of amyloid beta plaques in vivo. Nat Neurosci 2005; 8(4): 527–533.
38.Borthakur A, Gur T, Wheaton AJ,et al. In vivo measurement of plaque burden in a mouse model of Alzheimer's disease. J Magn Reson Imaging 2006 ,24(5):1011-7.
39. Faber C, Zahneisen B, Tippmann F,et al. Gradient-echo and CRAZED imaging for minute detection of Alzheimer plaques in an APPV717I x ADAM10-dn mouse model. Magn Reson Med. 2007 ,57(4):696-703.
40. Nakada Tsutomu, Matsuzawa Hitoshi,Igarashi Hironaka et al. In Vivo Visualization of Senile-Plaque-Like Pathology in Alzheimer's Disease Patients by MR Microscopy on a 7T System. J Neuroimaging. 2008 ,18(2):125-9.
1.Boska MD, Lewis TB, Destache CJ,et al. Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson’s disease.J Neurosci 2005; 25: 1691–1700.
2. Koga K, Mori A, Ohashi S,et al. H MRS identifies lactate rise in the striatum of MPTP-treated C57BL/6 mice. Eur J Neurosci 2006; 23: 1077–1081.
3. Brownell AL, Jenkins BG, Elmaleh DR,et al. Combined PET/MRS brain studies show dynamicand long-term physiological changes in a primate model of Parkinson disease. Nat Med 1998; 4: 1308–1312.
4. van Dellen A, Welch J, Dixon RM,et al. N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington’s disease mice. Neuroreport 2000; 11: 3751–3757.
5. Tsang TM,Woodman B, McLoughlin GA,et al. Metabolic characterization of the R6/2 transgenic mouse model of Huntington’s disease by highresolution MAS 1H NMR spectroscopy. J Proteome Res 2006; 5: 483–492.
6. Jenkins BG, Klivenyi P, Kustermann E,et al. Nonlinear decrease over time in N-acetylaspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington’s disease mice. J Neurochem 2000; 74: 2108–2119.
7. Andreassen OA, Jenkins BG, Dedeoglu A,et al. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation.J Neurochem 2001; 77: 383–390.
8. Choi JK,Jenkins BG, et al. Application of MRS to mouse models of neurodegenerative illness NMR Biomed 2007; 20: 216–237.
9 . Simmons ML, Frondoza CG, Coyle JT. Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 1991; 45: 37–45.
10. Urenjak J, Williams SR, Gadian DG,et al. Specific expression of N-acetylaspartate in neurons, oligodendrocyte- type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 1992; 59: 55–61.
11. Urenjak J, Williams SR, Gadian DG,et al. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993; 13: 981–989.
12.Burgess BL, McIsaac SA,Naus KE et al . Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer's disease mouse models with abundant A beta in plasma. Neurobiol Dis,2006,24:114-27.
13.Dedeoglu A, Choi JK, Cormier K, et al.Magnetic resonance spectroscopic analysis of Alzheimer's disease mouse brain that express mutant human APP shows altered neurochemical profile. Brain Res 2004;1012:60-65.
14.Marjanska M, Curran GL, Wengenack TM,et al. Monitoring disease progression in transgenic mouse models of Alzheimer's disease with proton magnetic resonance spectroscopy. Proc Natl Acad Sci U. S. A. 2005;102: 11906-11910.
15.von Kienlin M, Kunnecke B, Metzger F , et al.Altered metabolic profile in the frontal cortex of PS2APP transgenic mice, monitored throughout their life span. Neurobiol Dis 2005;18:32-39.
16.Oberg J,Spenger C, Wang FH,et al. Age related changes in brain metabolites observed by 1H MRS in APP/PS1 mice. Neurobiol Aging 2007.
17. Krishnan KR, Charles HC, Doraiswamy PM, et al. Randomized, placebocontrolled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease.Am. J. Psychiatry ,2003,160:2003–2011.
18.Ross BD, Hoang TQ, Bluml S,et al. In vivo magnetic resonance spectroscopy of human fetal neural transplants. NMR Biomed 1999; 12: 221–236.
19. Clifford R. Jack, Jr, Malgorzata Marjanska, Thomas M. Wengenack, et al. Magnetic Resonance Imaging of Alzheimer's Pathology in the Brains of Living Transgenic Mice: ANew Tool in Alzheimer's Disease Research. The Neuroscientist,2007,13:38-48 .
20. Constans JM, Meyerhoff DJ, Gerson J, et al. 1H MR spectroscopic imaging of white matter signal hyperintensities:Alzheimer disease and ischemic vascular dementia. Radiology 1995;197:517-523.
21. MacKay S, Ezekiel F, Di Sclafani V, et al. Alzheimer disease and subcortical ischemic vascular dementia:evaluation by combining MR imaging segmentation and H-1 MR spectroscopic imaging. Radiology 1996;198:537-545.
22. Kizu O, Yamada K, Ito H, et al. Posterior cingulate metabolic changes in frontotemporal lobar degeneration detected by magnetic resonance spectroscopy. Neuroradiology 2004;46:277-281.
23. Frederick BD, Lyoo IK, Satlin A, et al. In vivo proton magnetic resonance spectroscopy of the temporal lobe in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:1313-1322.
24. Kantarci K, Petersen RC, Boeve BF, et al. 1H MR spectroscopy in common dementias. Neurology 2004;63:1393-1398.
25. Chantal S, Braun CM, Bouchard RW, et al. Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial temporal lobes of patients with mild cognitive impairment and Alzheimer disease. Brain Res 2004;1003:26-35.
26.Satlin A, Bodick N, Offen WW, et al. Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer’s disease: changes after treatment with xanomeline,an M1 selective cholinergic agonist. Am J Psychiatry 1997;154:1459-1461.
1.Wimo A ,Winblad B,Aguero-Torres H , et al. The magnitude of dementia occurrence in the world . Alzheimer Dis Assoc Disord 2003 , 17 (2) : 632-67.
2.洪震.我国阿尔茨海默病的研究现状及展望.中华神经科杂志, 2001 , 34 (4) :193-195.
3.赵喜平著磁共振成像北京:科学出版社
4 . Simmons ML, Frondoza CG, Coyle JT. Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies. Neuroscience 1991; 45: 37–45.
5. Urenjak J, Williams SR, Gadian DG,et al. Specific expression of N-acetylaspartate in neurons, oligodendrocyte- type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 1992; 59: 55–61.
6. Urenjak J, Williams SR, Gadian DG,et al. Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993; 13: 981–989.
7. Shonk TK, Moats RA, Gifford P,et al. Probable Alzheimer disease: diagnosis with proton MR spectroscopy . Radiology 1995; 195: 65–72.
8. Dunlop DS, Mc Hale DM, Lajtha A. Decreased brain N-acetylaspartate in Huntington’s disease. Brain Res 1992; 580: 44–48.
9. Mathews PM, Andermann F, Silver K, et al. Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyo- pathies.Neurology 1993; 43: 2484–2490.
10. Fenstermacher MJ, Narayana PA. Serial proton magnetic resonance spectroscopy of ischemic brain injury in humans. Invest Radiol 1990; 25: 1034–1039.
11. Higuchi T, Fernandez EJ, Maudsley AA,et al. Mapping of lactate and N-acetyl-L-aspartate predicts infarction during acute focal ischemia: in vivo1H magnetic resonance spectroscopy in rats. Neurosurgery 1996; 38: 121–129.
12. Birken DL, Oldendorf WH. N-Acetyl-L-aspartic acid: a literature review of a compound prominent in 1H-NMR spectroscopic studies of brain. Neurosci. Biobehav Rev. 1989; 13: 23–31.
13. Taylor DL, Davies SE, Obrenovitch TP,et al. Investigation into the role of N-acetylaspartate in cerebral osmoregulation. J Neurochem 1995; 65: 275–281.
14. Baslow MH. Evidence supporting a role for N-acetyl-L-aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytical review. Neurochem Int 2002; 40:295–300.
15. Baslow MH. Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation. J Mol Neurosci 2003; 21: 185–190.
16. Choi IY, Gruetter R. Dynamic or inert metabolism ? Turnover of N-acetyl aspartate and glutathione from D-[1-13C]glucose in the rat brain in vivo. J Neurochem 2004; 91: 778–787.
17. Podo F. Tumour phospholipid metabolism. NMR Biomed 1999;12: 413–439.
18. Mason GF, Pan JW, Ponder SL,et al. Detection of brain glutamate and glutamine in spectroscopic images at 4.1 T. Magn Reson Med 1994; 32: 142–145.
19. Bristol LA, Rothstein JD. Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Ann Neurol 1996; 39: 676–679.
20. Rothstein JD, Van Kammen M, Levey AI,et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995; 38: 73–84.
21. Andreassen OA, Jenkins BG, Dedeoglu A,et al. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem 2001; 77: 383–390.
22. Jenkins BG, Klivenyi P, Kustermann E,et al. Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington’s disease mice. J Neurochem 2000; 74: 2108–2119.
23. Prichard J, Rothman D, Novotny E,et al. Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci USA 1991; 88: 5829–5831.
24. Petroff OA, Graham GD, Blamire AM,et al. Spectroscopic imaging of stroke in humans: histopathology correlates of spectral changes. Neurology 1992; 42: 1349–1354.
25. Dager SR, Strauss WL, Marro KI,et al. Proton magnetic resonance spectroscopy investigation of hyperventilation in subjects with panic disorder and comparison subjects. Am J Psychiatry 1995; 152: 666–672.
26. Brand A, Richter-Landsberg C, Leibfritz D. Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 1993; 15: 289–298.
27.Thurston JH, Sherman WR, Hauhart RE, et al. myo-inositol: a newly identified nonnitrogenous osmoregulatory molecule in mammalian brain. Pediatr Res 1989; 26: 482–485.
28. Isaacks RE, Bender AS, Kim CY,et al. Effect of ammonia and methionine sulfoximine on myo-inositol transport in cultured astrocytes. Neurochem Res 1999; 24: 51–59.
29.M.B. Burg, E.D. Kwon, D. Kultz, Regulation of gene expression by hypertonicity.Annu Rev Physiol 1997;59:437–455.
30.Games D,Adams D,Alessandrini R,et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717Fβ-amyloid precursor protein.Nature 19953;73:523-527。
31.Hsaio K,Borchelt DR,Olson K,et al. Age related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins.Neuron 1995;15:1203-1218.
32.. Sturchler-Pierrat C,Abramowski D,Duke M,et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997;94:13287-13292
33. Sturchler-Pierrat C,Abramowski D,Duke M,et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA1997;94:13287-13292.
34. Duff K,Eckman C,Zehr C,et al.Increased amyloid-β42(43) in brains of mice experessing mutant presenilin 1. Nature 1996;383:710-713.
35. Holcomb L, Gordon MN, McGowan E,et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998;4(1):97– 100.
36. Herzig M.C, et al. Aβis targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 2004 :7954–960.
37. McGowan E. et al. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 2005;47:191–199.
38. Lewis J,Mc Gowan E,Rockwood J,et al. Neurofibrillary tangles,amyotrophy and progrssive motor disturbance in mice expressing mutant(P301L)tau protein. Nat Genet 2000;25:402-405.
39.Allen B,et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 2002;22:9340–9351.
40. Tanemura K,et al.Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol Dis 2001 8:1036–1045.
41. Tatebayashi Y, et al. Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad. Sci 2002;99:13896–13901.
42. SantaCruz K,et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481.
43. Andorfer C,et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 2003;86:582–590.
44. Lewis J,Dickson DW,Lin W-L,et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001;293:1487-1491.
45.Salvatore Oddo,Antonella Caccamo,Masashi Kitazawa,et al Amyloid depositionprecedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiology of Aging,2003;24:1063-1070.
46.Dedeoglu A, Choi JK, Cormier K, et al.Magnetic resonance spectroscopic analysis of Alzheimer's disease mouse brain that express mutant human APP shows altered neurochemical profile. Brain Res 2004;1012:60-65.
47.Marjanska M, Curran GL, Wengenack TM,et al. Monitoring disease progression in transgenic mouse models of Alzheimer's disease with proton magnetic resonance spectroscopy. Proc Natl Acad Sci U. S. A. 2005;102: 11906-11910.
48.von Kienlin M, Kunnecke B, Metzger F , et al.Altered metabolic profile in the frontal cortex of PS2APP transgenic mice, monitored throughout their life span. Neurobiol Dis 2005;18:32-39.
49.Oberg J,Spenger C, Wang FH,et al. Age related changes in brain metabolites observed by 1H MRS in APP/PS1 mice. Neurobiol Aging 2007.
50.Choi JK,Jenkins BG, et al. Application of MRS to mouse models of neurodegenerative illness NMR Biomed 2007; 20: 216–237.
51.Doraiswamy M, Charles C, Krishnan R,et al.Prediction of cognitive decline in early Alzheimer’s disease. Lancet 1998;352:1678.
52.Parnetti L, Tarducci R, Presciutti O, et al. Proton magnetic resonance spectroscopy can differentiate Alzheimer’s disease from normal aging. Mech Ageing Dev 1997;97:9-14.
53.Schuff N, Capizzano AA, Du AT, et al. Selective reduction of N-acetylaspartate in medial temporal and parietal lobes in AD. Neurology 2002;58:928-935.
54.Kantarci K, Petersen RC, Boeve BF, et al. 1H MR spectroscopy in common dementias. Neurology 2004;63:1393-1398.
55 . Kizu O, Yamada K, Ito H, et al. Posterior cingulate metabolic changes in frontotemporal lobar degeneration detected by magnetic resonance spectroscopy. Neuroradiology 2004;46:277-281.
56.Moats RA, Ernst T, Shonk TK, et al. Abnormal cerebral metabolite concentrations in patients with probable Alzheimer disease. Magn Reson Med 1994; 32:110-115.
57.Frederick BD, Lyoo IK, Satlin A, et al. In vivo proton magnetic resonance spectroscopy of the temporal lobe in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:1313-1322.
58.Rai G, McConnell J, Waldman A, et al. Brain proton spectroscopy in dementia: an aid to clinical diagnosis. Lancet 1999;353:1063-1064.
59.Chantal S, Braun CM, Bouchard RW, et al. Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial temporal lobes of patients with mild cognitive impairment and Alzheimer disease. Brain Res 2004;1003:26-35.
60.Ackl N, Ising M, Schreiber YA, et al. Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 2005;384: 23-28.
61.Miller B, Moats R, Shonk T, et al. Alzheimer disease depiction of increased cerebral myoinositol with proton MR spectroscopy. Radiology 1993;187:433-437.
62.Parnetti L, Lowenthal DT, Presciutti O, et al. 1H-MRS,MRI-based hippocampal volumetry, and 99mTc-HMPAO-SPECT in normal aging, age-associated memory impairment, and probable Alzheimer’s disease.J Am Geriatr Soc 1996;44:133-138.
63. Jessen F, Block W, Traber F, et al. Proton MR spectroscopy detects a relative decrease of N-acetylaspartate in the medial temporal lobe of patients with AD. Neurology 2000;55:684-688.
64. Ernst T, Chang L, Melchor R, et al. Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe 1H MR spectroscopy. Radiology 1997;203:829-836.
65.Huang W, Alexander GE, Chang L, et al. Brain metabolite concentration and dementia severity in Alzheimer’s disease: a 1H MRS study. Neurology 2001;57:626-632.
66.Kantarci K, Jack Jr CR, Xu YC, et al. Regional metabolic patterns in mild cognitive impairment and Alzheimer’s disease: a 1H MRS study. Neurology 2000;55:210-217.
67. Shonk T, Moats R, Gifford P, et al. Probable Alzheimer disease: diagnosis with proton MR spectroscopy. Radiology 1995;195:65-72.
68. Constans JM, Meyerhoff DJ, Gerson J, et al. 1H MR spectroscopic imaging of white matter signal hyperintensities:Alzheimer disease and ischemic vascular dementia. Radiology 1995;197:517-523.
69. MacKay S, Ezekiel F, Di Sclafani V, et al. Alzheimer disease and subcortical ischemic vascular dementia:evaluation by combining MR imaging segmentation and H-1 MR spectroscopic imaging. Radiology 1996;198:537-545.
70. Meyerhoff D, MacKay S, Constans J, et al. Axonal injury and membrane alterations in Alzheimer’s disease suggested by in vivo proton magnetic resonance spectroscopic imaging. Ann Neurol 1994;36:40-47.
71. Pfefferbaum A, Adalsteinsson E, Spielman D, et al.In vivo brain concentration of N-acetyl compounds,creatine, and choline in Alzheimer’s disease. Arch Gen Psychiatry 1999;56:185-192.
72. Christensen P, Schlosser A, Henriksen O. Reduced N-acetylaspartate content in the frontal part of the brain in patients with probable Alzheimer’s disease. Magn Reson Imaging 1995;13:457-462.
73. Kantarci K, Jack Jr CR. Neuroimaging in Alzheimer disease: an evidence-based review. Neuroimaging Clin N Am 2003;13:197-209.
74. Rose SE, de Zubicaray GI, Wang D, et al. A 1H MRS study of probable Alzheimer’s disease and normal aging: implications for longitudinal monitoring of dementia progression. Magn Reson Imaging 1999;17:291-299.
75. Schuff N, Amend D, Ezekiel F, et al. Changes of hippocampal N-acetyl aspartate and volume in Alzheimer’s disease. A proton MR spectroscopic imaging and MRI study. Neurology 1997;49:1513-1521.
76. Bottomley P, Cousins J, Pendrey D, et al. Alzheimer dementia: quantification of energy metabolism and mobile phosphoesters with P-31 NMR spectroscopy. Radiology1992;183:695-699.
77.Burri R, Bigler P, Straehl P, et al. Brain development: 1H magnetic resonance spectroscopy of rat brain extracts compared with chromatographic methods. Neurochem Res 1990;15:1009-1016.
78. Satlin A, Bodick N, Offen WW, et al. Brain proton magnetic resonance spectroscopy (1H-MRS) in Alzheimer’s disease: changes after treatment with xanomeline,an M1 selective cholinergic agonist. Am J Psychiatry 1997;154:1459-1461.
79. Klunk WE, Xu C, Panchalingham K, McClure RJ, Pettegrew JW Quantitative 1H and 31P MRS of PCA extracts of postmortem Alzheimer_s disease brain. Neurobiol Aging 1996;17:349-357
80. Modrego PJ, Fayed N, Pina MA Conversion from mild cognitive impairment to probably Alzheimer_s disease predicted by brain magnetic resonance spectroscopy. Am J Psychiatry 2005;162: 667-675
81. Falini A, Bozzali M, Magnani G, et al. A whole brain MR spectroscopy study from patients with Alzheimer_s disease and mild cognitive impairment. Neuroimage 2005;26:1159-1163.
82.Krishnan KR, Charles HC, Doraiswamy PM, et al. Randomized, placebocontrolled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer’s disease.Am. J. Psychiatry ,2003,160:2003–2011.
83.Ross BD, Hoang TQ, Bluml S,et al. In vivo magnetic resonance spectroscopy of human fetal neural transplants. NMR Biomed 1999; 12: 221–236.
84. Clifford R. Jack, Jr, Malgorzata Marjanska, Thomas M. Wengenack, et al. Magnetic Resonance Imaging of Alzheimer's Pathology in the Brains of Living Transgenic Mice: A New Tool in Alzheimer's Disease Research. The Neuroscientist,2007,13:38-48