本文選題：阿爾茨海默病 + 5XFAD小鼠　； 參考：《東南大學(xué)》2017年博士論文

【摘要】：研究背景阿爾茨海默病(Alzheimer's disease,AD),又稱老年性癡呆,是最常見的老年期癡呆。目前AD病因不清,發(fā)病機(jī)制不明,起病隱匿,缺乏明確的診斷標(biāo)志物,尚無有效根治措施。早期診斷與及時(shí)干預(yù)是延緩AD疾病進(jìn)展的關(guān)鍵措施。AD的診斷標(biāo)準(zhǔn)開始于1984年,近年來不斷修訂,2011年至今新修訂的AD診斷標(biāo)準(zhǔn)采用“情節(jié)記憶功能受損”結(jié)合“AD生物標(biāo)志物異常”的新診斷模式,將AD定義為一個(gè)包含臨床前期(preclinicalAD)、輕度認(rèn)知障礙期(mild cognitive impairment due to AD)與阿爾茨海默病癡呆期(dementia due to AD)的延續(xù)疾病譜。然而,目前現(xiàn)有的生物標(biāo)志物檢測(cè)在AD早期階段的臨床可行性較低。因此,尋找AD早期階段新的生物標(biāo)志物,為AD治療打開關(guān)鍵的時(shí)間窗是AD研究的熱點(diǎn)。磁共振成像(magnetic resonance imaging,MRI)具有無創(chuàng)傷、可重復(fù)性、時(shí)間/空間分辨率高、成像快速、成本相對(duì)較低等優(yōu)點(diǎn),已成為目前探討AD生物標(biāo)志物的核心工具之一。研究發(fā)現(xiàn)的可輔助AD診斷的MRI生物標(biāo)記物主要分為結(jié)構(gòu)和功能兩大類,如以海馬為主的內(nèi)側(cè)顳葉結(jié)構(gòu)萎縮和后扣帶功能代謝改變。然而,以AD患者為對(duì)象的研究通常始于疾病的中晚期,對(duì)于AD發(fā)病早期不能進(jìn)行深入地研究。因此轉(zhuǎn)基因AD實(shí)驗(yàn)動(dòng)物為AD疾病早期的研究提供了理想的模型。此外,近年來隨著高場(chǎng)強(qiáng)動(dòng)物磁共振(micro-MRI)的出現(xiàn),進(jìn)一步提高了早期AD診斷的敏感性,并可進(jìn)一步探討AD行為學(xué)改變、MRI特征與病理改變之間的關(guān)系。因此,本研究選擇攜帶5個(gè)家族性基因突變的APP/PS1轉(zhuǎn)基因模型小鼠(transgenic mice with five familial AD,5XFAD)和正常野生型 C57BL/6 小鼠為研究對(duì)象,采用多維度動(dòng)物行為學(xué)測(cè)試評(píng)估其情感和認(rèn)知功能,繼而,結(jié)合7.0T高場(chǎng)強(qiáng)動(dòng)物多模態(tài)MRI (T2加權(quán)結(jié)構(gòu)成像、T2map成像和錳增強(qiáng)磁共振成像)進(jìn)行縱向隨訪研究,主要探討(1) 5XFAD小鼠疾病早期是否存在腦組織微結(jié)構(gòu)完整性改變?腦組織微結(jié)構(gòu)改變是否隨著疾病進(jìn)展加重?腦組織微結(jié)構(gòu)改變是否與情感和/或認(rèn)知障礙相關(guān)?(2)5XFAD小鼠疾病早期是否存在神經(jīng)元活性改變?腦功能改變是否隨著疾病進(jìn)展加重?腦功能改變是否與情感和/或認(rèn)知障礙相關(guān)?最終,希望通過以上兩部分研究加深我們對(duì)AD早期情感和/或認(rèn)知功能損害的神經(jīng)網(wǎng)絡(luò)機(jī)制的了解,為尋找AD早期階段MRI生物標(biāo)記物提供動(dòng)物層面的依據(jù)。第一部分5XFAD小鼠早期腦組織微結(jié)構(gòu)完整性及其對(duì)空間認(rèn)知功能影響的研究目的:探討5XFAD小鼠早期腦組織微結(jié)構(gòu)完整性損害模式及其與空間認(rèn)知功能的關(guān)系。方法:(1)本研究采用1、2、3和5月齡四個(gè)時(shí)間點(diǎn)的5XFAD模型小鼠和野生型C57BL/6小鼠,采用蔗糖水偏愛實(shí)驗(yàn)、曠場(chǎng)實(shí)驗(yàn)、高架十字迷宮實(shí)驗(yàn)和Morris水迷宮實(shí)驗(yàn)對(duì)動(dòng)物進(jìn)行行為學(xué)評(píng)估。(2)用7.0Tmicro-MRI完成每個(gè)時(shí)間點(diǎn)兩組小鼠的多模態(tài)腦成像(T2加權(quán)和T2map)。分別采用基于體素的分析方法(voxel-based analysis,VBA)和感興趣區(qū)分析方法(region of interest,ROI)對(duì)比分析各時(shí)間點(diǎn)5XFAD小鼠和野生型小鼠灰質(zhì)腦區(qū)的T2弛豫時(shí)間值(T2 relaxation time,T2)差異。此外,利用ROI進(jìn)一步分析海馬各亞區(qū):背側(cè)海馬角/安蒙角1區(qū)(cornu Ammonisl,CA1)、背側(cè)海馬角3區(qū)(CA3)、背側(cè)齒狀回(dentate gyrus, DG)、腹側(cè)CA1、腹側(cè)CA3和腹側(cè)DG)的T2值和體積。(3)通過相關(guān)分析評(píng)價(jià)海馬各亞區(qū)的T2值與認(rèn)知評(píng)分之間的相關(guān)性。結(jié)果:(1)行為學(xué)結(jié)果:1、2、3和5月齡的5XFAD小鼠和野生型小鼠在蔗糖水偏愛實(shí)驗(yàn)、曠場(chǎng)實(shí)驗(yàn)和高架十字迷宮實(shí)驗(yàn)中的行為學(xué)表現(xiàn)無明顯差異。Morris水迷宮結(jié)果:與同月齡野生型小鼠相比,1月齡5XFAD小鼠前5天學(xué)習(xí)訓(xùn)練期的潛伏期時(shí)間無明顯差異,第6天記憶檢測(cè)過程中目標(biāo)象限停留時(shí)間明顯減少(p = 0.0365) ; 2和3月齡5XFAD小鼠學(xué)習(xí)訓(xùn)練期第3天至站臺(tái)的潛伏期時(shí)間延長(zhǎng)(p= 0.0024, 0.0300),記憶檢測(cè)過程中目標(biāo)象限停留時(shí)間明顯減少(P 0.001, = 0.011) : 5月齡5XFAD小鼠學(xué)習(xí)訓(xùn)練期第3、4和5天至站臺(tái)的潛伏期時(shí)間延長(zhǎng)(p = 0.0154, 0.0154, 0.0011),記憶檢測(cè)過程中目標(biāo)象限停留時(shí)間明顯減少(= 0.034)。(2) MRI結(jié)果:與同月齡野生型小鼠相比,1月齡5XFAD小鼠各腦區(qū)的T2值無明顯差異;VBA和ROI兩種方法都顯示2、3和5月齡的5XFAD小鼠海馬區(qū)(hippocampus,Hip) T2值明顯降低(p=0.0420,0.0182, 0.0001),此外,VBA還顯示5月齡的5XFAD小鼠的前扣帶皮層(the cingulate cortex,cg)和杏仁核(amygdala,Amy)的 T2值降低(p 0.05)。海馬各亞區(qū)ROI分析顯示:2和3月齡的5XFAD小鼠的背側(cè)CA1、CA3、DG和腹側(cè)CA1的 T2 值明顯降低(2 月齡:p = 0.0214, 0.0030, 0.0369,0.0369; 3 月齡:p = 0.0119,0.0031,0.0119, 0.0119),5月齡的 5XFAD小鼠的背腹側(cè) CA1、CA3、和 DG的 T2值均明顯降低(p = 0.0045, 0.001,0.0036,0.0007,0.0001,0.0045)。1、2、3和 5月齡的5XFAD小鼠海馬各亞區(qū)體積與野生型小鼠相比無明顯差異。(3)相關(guān)分析結(jié)果:3和5月齡的5XFAD小鼠背側(cè)CA1及5月齡5XFAD小鼠背側(cè)DG區(qū)的T2值與水迷宮實(shí)驗(yàn)的第5天潛伏期負(fù)相關(guān)(r = -0.6188, -0.5190,-0.5240),2、3和5月齡的5XFAD小鼠背側(cè)CA1的T2值與水迷宮實(shí)驗(yàn)的目標(biāo)象限停留時(shí)間正相關(guān)(r = 0.6144,0.6645, 0.5629);腹側(cè)海馬各亞區(qū)的T2值均沒有發(fā)現(xiàn)與這兩者相關(guān)。結(jié)論:5XFAD小鼠早期存在海馬區(qū)組織微結(jié)構(gòu)完整性受損,并隨疾病進(jìn)展加重。背側(cè)海馬區(qū)組織微結(jié)構(gòu)完整性損害與其空間認(rèn)知功能狀態(tài)相關(guān)。本研究從動(dòng)物模型在體影像的層面證實(shí)了海馬在AD早期的重要作用,且背側(cè)海馬的T2值可能成為輔助AD早期診斷及監(jiān)測(cè)AD進(jìn)展的生物標(biāo)記物之一。第二部分5XFAD小鼠早期腦神經(jīng)元活性及其對(duì)空間認(rèn)知功能影響的研究目的:探討5XFAD小鼠早期腦神經(jīng)元活性改變模式及其與空間認(rèn)知功能的關(guān)系。方法:(1)本研究采用1、2、3和5月齡四個(gè)時(shí)間點(diǎn)的5XFAD模型小鼠和野生型C57BL/6小鼠,采用蔗糖水偏愛實(shí)驗(yàn)、曠場(chǎng)實(shí)驗(yàn)、高架十字迷宮實(shí)驗(yàn)和Morris水迷宮實(shí)驗(yàn)對(duì)動(dòng)物進(jìn)行(基線期)行為學(xué)評(píng)估。(2)利用7.0Tmicro-MRI完成每個(gè)時(shí)間點(diǎn)兩組小鼠的基線期T1加權(quán)成像(T1 weighted imaging,T1WI);繼而腹腔注射Mnc12溶液,間隔24小時(shí),共注射4次(每次13.95 mg/kg),最后一次注射后24小時(shí)進(jìn)行錳強(qiáng)磁共振成像(manganese-enhanced magnetic resonance imaging,MEMRI)。(3) MEMRI 成像后每天觀察兩組小鼠日常行為狀態(tài),并于首次注射MJncl2溶液后12天再次完成曠場(chǎng)實(shí)驗(yàn)和Morris水迷宮實(shí)驗(yàn)。(4)利用ROI對(duì)比分析各時(shí)間點(diǎn)5XFAD小鼠和野生型小鼠灰質(zhì)腦區(qū)的信號(hào)強(qiáng)度值(signal intensity,SI)差異,其中同一只小鼠注射Mnc12前后的兩次T1WI的平均信號(hào)強(qiáng)度差值[SI=100% × (SI注射錳后- SI基線期)/SI基線期] 作為反映MR2+聚集濃度的指標(biāo)。(5)通過相關(guān)分析評(píng)價(jià)ROI的信號(hào)強(qiáng)度值與認(rèn)知評(píng)分之間的相關(guān)性。結(jié)果:(1)行為學(xué)結(jié)果:1、2、3和5月齡的5XFAD小鼠和野生型小鼠在蔗糖水偏愛實(shí)驗(yàn)、曠場(chǎng)實(shí)驗(yàn)和高架十字迷宮實(shí)驗(yàn)的行為學(xué)表現(xiàn)無明顯差異。Morris水迷宮結(jié)果:與野生型小鼠相比,1月齡5XFAD小鼠前5天的學(xué)習(xí)訓(xùn)練期的潛伏期時(shí)間無明顯差異,第6天記憶檢測(cè)過程中目標(biāo)象限停留時(shí)間明顯減少(p=0.0365) ; 2和3月齡5XFAD小鼠學(xué)習(xí)訓(xùn)練期第3天至站臺(tái)的潛伏期時(shí)間延長(zhǎng)(p=0.0024 , 0.0300),記憶檢測(cè)過程中目標(biāo)象限停留時(shí)間明顯減少(p 0.001,= 0.011) ; 5月齡5XFAD小鼠學(xué)習(xí)訓(xùn)練期第3、4和5天至站臺(tái)的潛伏期時(shí)間延長(zhǎng)(p = 0.0154,0.0154,0.0011),記憶檢測(cè)過程中目標(biāo)象限停留時(shí)間明顯減少(p = 0.034)。(2) MRI結(jié)果:與同月齡野生型小鼠相比,1月齡5XFAD小鼠各腦區(qū)的SI值無明顯差異;2月齡5XFAD小鼠海馬區(qū)(Hip)SI值明顯增加(p = 0.0167); 3月齡5XFAD小鼠海馬區(qū)和內(nèi)嗅皮層區(qū)(entorhinal cortex,ERC) SI 值明顯增加(= 0.0107,0.0684); 5 月齡 5XFAD 小鼠尾殼核(caudate-putamen,CPu)、壓后皮層區(qū)(theretrosplenial cortex, RSC)、HIP 和 ERC 的 SI 值明顯增加(= 0.0228,0.0795,0.0167, 0.0684)。(3)相關(guān)分析結(jié)果:5 月齡 5XFAD 小鼠Hip的SI值與水迷宮實(shí)驗(yàn)的第5天潛伏期正相關(guān)(r = 0.8668)。3和5月齡的5XFAD小鼠Hip的SI值與水迷宮實(shí)驗(yàn)的目標(biāo)象限停留時(shí)間負(fù)相關(guān)(r = -0.8269,-0.8364) ; 2、3和5月齡的5XFAD小鼠ERC的SI值與目標(biāo)象限停留時(shí)間負(fù)相關(guān)(r = -0.9204, -0.8576, -0.8386)。各月齡的野生型小鼠Hip和ERC的SI值均沒有發(fā)現(xiàn)與這兩者相關(guān)。結(jié)論:5XFAD小鼠早期存在認(rèn)知相關(guān)腦區(qū)(特別是海馬和內(nèi)嗅皮層)的神經(jīng)元活性增加,并隨疾病進(jìn)展明顯加重。海馬和內(nèi)嗅皮層的神經(jīng)元活性與其空間認(rèn)知功能狀態(tài)相關(guān)。本研究從動(dòng)物模型在體影像的層面證實(shí)了海馬和內(nèi)嗅皮層在AD早期階段的重要作用,且早期神經(jīng)元活性可能成為輔助AD早期診斷的生物標(biāo)記物之一。
[Abstract]:Alzheimer's disease (AD), also known as Alzheimer's disease, is the most common senile dementia. At present, the etiology of AD is unclear, the pathogenesis is unknown, the onset of the disease is hidden, there is no clear diagnostic marker, and there is no effective radical cure. Early diagnosis and time intervention are the key measures to delay the progress of AD disease, the diagnostic mark of.AD. Starting in 1984, it has been revised in recent years. From 2011 to date, the newly revised AD diagnostic standard uses the new diagnostic model of "impaired episodic memory function" combined with "AD biomarker anomaly", and defines AD as a period containing the preclinical (preclinicalAD), the mild cognitive impairment (mild cognitive impairment due to AD) and the Artz sea The persistent disease spectrum of dementia due to AD. However, the clinical feasibility of existing biomarker detection at the early stage of AD is low. Therefore, finding new biomarkers at the early stage of AD and opening the key time window for AD treatment are the hot spots of AD research. Magnetic resonance imaging (magnetic resonance imaging, MRI) has a low clinical feasibility. No trauma, repeatability, high time / space resolution, rapid imaging and low cost, it has become one of the core tools to explore AD biomarkers. The MRI biomarkers that can be diagnosed by AD are divided into two major categories, structure and function, such as the atrophy of the medial temporal lobe and the posterior cingulate of the hippocampus. Functional metabolic changes. However, the study of AD patients usually begins in the middle and late stages of the disease and can not be deeply studied in the early stages of the onset of AD. Therefore, transgenic AD experimental animals provide an ideal model for the early study of AD disease. In addition, in recent years, with the emergence of high field dynamic magnetic resonance (micro-MRI), it has been further improved. The sensitivity of early AD diagnosis can be further explored in the relationship between AD behavioral changes, MRI characteristics and pathological changes. Therefore, this study selected 5 familial gene mutations in APP/PS1 transgenic mice (transgenic mice with five familial AD, 5XFAD) and normal wild type C57BL/6 mice. Animal behavioral tests assess their emotional and cognitive functions, and then combine 7.0T high field animals with multimodal MRI (T2 weighted structural imaging, T2map imaging and manganese enhanced magnetic resonance imaging) for longitudinal follow-up studies. (1) whether there is a change in brain tissue integrity in the early stage of the disease of 5XFAD mice and the change in the microstructure of the brain tissue Is the brain tissue changes associated with emotional and / or cognitive impairments? (2) is there a change in neuronal activity in the early stage of the 5XFAD mouse disease? Is brain function change aggravated with disease progression? Is brain function change associated with emotion and / or cognitive impairment? Finally, hope to deepen the study through the above two parts Our understanding of the neural network mechanism of AD early emotion and / or cognitive impairment provides the basis for finding the animal level for the early stage of AD MRI biomarkers. Part 1 the study of the early brain microstructure integrity and its effect on spatial cognitive function in the early part of the 5XFAD mice: To explore the early brain tissue microstructure in the 5XFAD mice. The relationship between the pattern of integrality damage and its spatial cognitive function. Methods: (1) this study uses 5XFAD model mice and wild type C57BL/6 mice with 1,2,3 and 5 month old time points, using sucrose water preference experiment, open field experiment, elevated cross maze experiment and Morris water maze test to evaluate the behavior of animals. (2) 7.0Tmicro-MRI finished with 7.0Tmicro-MRI The multimodal brain imaging (T2 weighted and T2map) of two groups of mice at each time point were compared with the voxel based analysis (voxel-based analysis, VBA) and the region of interest analysis (region of interest, ROI), respectively, to analyze the T2 relaxation time values of the gray matter brain regions of 5XFAD mice and wild type mice at each time point. In addition, ROI was used to further analyze the value and volume of the hippocampal subregions: dorsal hippocampal corner / amono angle 1 (cornu Ammonisl, CA1), dorsal hippocampal angle 3 (CA3), dorsal dentate gyrus (dentate gyrus, DG), ventral CA1, ventral CA3 and ventral DG). (3) correlation analysis was used to evaluate the correlation between the values of the hippocampus subregions and the cognitive score. Fruit: (1) behavioral results: there was no significant difference in behavioral performance between 1,2,3 and 5 month old 5XFAD mice and wild type mice in sucrose water preference experiment, open field experiment and elevated cross maze test. Compared with the same month old wild type mice, there was no significant difference in the latency time of the training period of the 1 month old 5XFAD mice in the first 5 days. In the process of sixth day memory detection, the residence time of the target quadrant decreased significantly (P = 0.0365); the incubation period of the 2 and 3 month old 5XFAD mice was prolonged from third days to the platform (p= 0.0024, 0.0300), and the target quadrant residence time in the memory detection process was significantly reduced (P 0.001, = 0.011): 5 month old 5XFAD mice learning training period 3,4 The latency of the 5 days to the platform was prolonged (P = 0.0154, 0.0154, 0.0011), and the target quadrant time in the memory detection process was significantly reduced (= 0.034). (2) MRI results: compared with the same month old wild type mice, the T2 values in the brain regions of 1 month old 5XFAD mice were not significantly different; the VBA and ROI two methods showed 2,3 and 5 month old 5XFAD mice hippocampus. The T2 value of the region (hippocampus, Hip) decreased significantly (p=0.0420,0.0182, 0.0001). In addition, VBA also showed that the anterior cingulate cortex of 5 month old 5XFAD mice (the cingulate cortex, CG) and amygdala (amygdala, Amy) decreased (0.05). Significantly decreased (2 month old: P = 0.0214, 0.0030, 0.0369,0.0369; 3 month old: P = 0.0119,0.0031,0.0119, 0.0119), and 5 month old of 5XFAD mice on the dorsal ventral CA1, CA3, and DG significantly decreased (P = 0.0045, 0.001,0.0036,0.0007,0.0001,0.0045).1,2,3 and 5 month old of the hippocampal subregions of.1,2,3 and 5 month old were less obvious than those of wild type mice. (3) correlation analysis results: 3 and 5 month old of the dorsal CA1 and 5 month old 5XFAD mice in the dorsal side of the 5XFAD mice were negatively correlated with the fifth day incubation period of the water maze test (r = -0.6188, -0.5190, -0.5240). 2,3 and 5 month old 5XFAD mouse dorsal CA1 was positively correlated with the target quadrant time of the water maze experiment. 0.5629): the T2 values in the subregions of the ventral hippocampal subregions were not found to be related to the two. Conclusion: the microstructural integrity of the hippocampal tissue was impaired in the early hippocampal tissue in the 5XFAD mice and increased with the progression of the disease. The tissue integrity damage in the dorsal hippocampus was related to its spatial cognitive function. The important role of hippocampus in the early AD, and the T2 value of the dorsal hippocampus may be one of the biomarkers to assist the early diagnosis of AD and monitor the progress of AD. The study of the early brain neuron activity and its influence on spatial cognitive function of the second part of 5XFAD mice: To explore the pattern of early brain neuron activity change and its space in 5XFAD mice. Methods: (1) the study adopted 5XFAD model mice and wild type C57BL/6 mice with four time points of 1,2,3 and 5 month old. Using sucrose water preference experiment, open field experiment, elevated cross maze experiment and Morris water maze experiment, the animal (baseline) behavior assessment was carried out. (2) each time was completed by 7.0Tmicro-MRI. The baseline T1 weighted imaging (T1 weighted imaging, T1WI) of the two groups of mice was followed by intraperitoneal injection of Mnc12 solution, 24 hours interval, 4 times (13.95 mg/kg per time), and 24 hours after the last injection (manganese-enhanced magnetic resonance imaging, MEMRI). (3) two mice were observed every day after the imaging. After the first injection of MJncl2 solution, 12 days after the first injection, the open field experiment and the Morris water maze experiment were completed again. (4) the difference between the signal intensity (signal intensity, SI) of the gray matter brain regions of the 5XFAD mice and the wild type mice at each time point was contrasted with ROI, and the average signal intensity of two times before and after the injection of Mnc12 in the same mouse was observed. The degree difference [SI=100% x (SI after SI baseline SI baseline period) /SI baseline] as an indicator to reflect the concentration of MR2+ aggregation. (5) correlation analysis was used to evaluate the correlation between the signal intensity values of ROI and the cognitive score. Results: (1) behavioral results: 1,2,3 and 5 month old 5XFAD mice and wild mice in sucrose water preference experiment, open field experiment and There was no significant difference in the behavioral performance of the elevated cross maze experiment with.Morris water maze. Compared with the wild type mice, there was no significant difference in the latency time of the 1 month old 5XFAD mice at the first 5 days of the learning and training period, and the target quadrant residence time in the sixth day memory detection was significantly reduced (p=0.0365); 2 and 3 month old 5XFAD mice were in the training period. The latency time of the 3 days to the platform was prolonged (p=0.0024, 0.0300). The retention time of target quadrants in the memory detection process was significantly reduced (P 0.001, = 0.011), and the latency time of the 3,4 and 5 days to the platform was prolonged (P = 0.0154,0.0154,0.0011) in the learning and training period of 5 month old 5XFAD mice, and the retention time of the target quadrant in the memory detection process was significantly reduced (P = 0.034) (2) (2) MRI results: compared with the same month old wild type mice, there was no significant difference in the SI value of the brain regions of 1 month old 5XFAD mice; the SI value of the hippocampus (Hip) of the 2 month old 5XFAD mice increased significantly (P = 0.0167); the 3 month old 5XFAD mice hippocampus and the inner olfactory cortex region (entorhinal cortex, ERC) significantly increased (= 5 month old); 5 month old mice Caudate-putamen (CPu), theretrosplenial cortex, RSC, SI value of HIP and ERC increased significantly (= 0.0228,0.0795,0.0167, 0.0684). (3) correlation analysis results: 5 month old 5XFAD mice Hip SI values were positively correlated with the fifth day incubation period of water maze experiment (0.8668) and 5 month old The target quadrant time of the labyrinth experiment was negative correlation (r = -0.8269, -0.8364); the SI value of ERC in 2,3 and 5 month old of 5XFAD mice was negatively correlated with the stay time of the target quadrant (r = -0.9204, -0.8576, -0.8386). Neuronal activity in the brain region (especially in the hippocampus and the olfactory cortex) increased significantly with the progression of the disease. The activity of neurons in the hippocampus and the inner olfactory cortex was related to the state of spatial cognitive function. This study demonstrated the important role of the hippocampus and the olfactory cortex at the early stage of AD from the animal model at the body image level, and the early neuronal activity. Sex may be one of the biomarkers for early diagnosis of AD.
【學(xué)位授予單位】：東南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R749.16;R-332

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