發(fā)布時(shí)間：2018-07-07 14:44

  本文選題：阿爾茨海默病 + 輕度認(rèn)知功能障礙　； 參考：《河北醫(yī)科大學(xué)》2012年碩士論文

【摘要】：阿爾茨海默病（Alzheimer’s disease，AD）是發(fā)生于老年和老年前期、以進(jìn)行性認(rèn)知功能障礙和行為損害為特征的中樞神經(jīng)系統(tǒng)退行性病變，是老年期癡呆的最常見(jiàn)類型，主要表現(xiàn)為進(jìn)行性全面認(rèn)知功能損害。輕度認(rèn)知功能障礙（Mild cognitive impairment，MCI）被認(rèn)為是AD的臨床前期，指記憶力受損但尚未達(dá)到癡呆的程度。我國(guó)60歲以上老年人口有1.2億，癡呆患病率為3~8%，其中60%以上為阿爾茨海默病，以此比例，在我國(guó)估計(jì)有400~500萬(wàn)AD患者。 帕金森�。≒arkinson disease，PD），又名震顫麻痹（shaking palsy，paralysis agitans）是一種常見(jiàn)于中老年的神經(jīng)系統(tǒng)變性疾病，于1817年由英國(guó)醫(yī)生James Parkinson首先系統(tǒng)的進(jìn)行描述故而得名。PD的發(fā)病年齡在40~70歲之間，其中，，50~60歲為發(fā)病高峰。我國(guó)55歲~65歲人群患病率為約1%，隨著年齡增高而升高，男性稍高于女性。 隨著人口老齡化進(jìn)程，阿爾茨海默病和帕金森病的發(fā)病率均逐年上升。尤其AD已成為繼腫瘤、心血管疾病、腦血管疾病之后導(dǎo)致死亡的第四位疾病，二者均嚴(yán)重影響患者的生活質(zhì)量，給家庭、政府和社會(huì)帶來(lái)沉重的生活和經(jīng)濟(jì)負(fù)擔(dān)。 國(guó)內(nèi)外在AD領(lǐng)域多為動(dòng)物實(shí)驗(yàn)或尸檢后研究神經(jīng)元的受損情況，主要探討AD的發(fā)病與細(xì)胞凋亡、細(xì)胞周期失調(diào)等機(jī)制的內(nèi)在聯(lián)系。然而，早期診斷AD，發(fā)現(xiàn)MCI患者是制定治療策略、控制疾病進(jìn)程的基礎(chǔ)。近期研究表明，在AD中細(xì)胞凋亡、細(xì)胞周期調(diào)控的失調(diào)不僅局限于神經(jīng)元，而且體現(xiàn)在外周血淋巴細(xì)胞和成纖維細(xì)胞，淋巴細(xì)胞為研究細(xì)胞周期相關(guān)事件在AD發(fā)病機(jī)制中的作用和尋找可干預(yù)的靶點(diǎn)提供了方便有用的模型。 外周血采集方便，外周血淋巴細(xì)胞（peripheral blood lymphocytes，PBLs）是血液循環(huán)中的淋巴細(xì)胞。主要由T細(xì)胞（約占70%~80%）和B細(xì)胞（約占20%~30%）組成。因此，深入研究可能為早期診斷AD提供方便有效的外周標(biāo)記物和藥物干預(yù)的靶點(diǎn)。如果能從外周血中獲得簡(jiǎn)便、有效的標(biāo)志物將對(duì)AD早期診斷及治療產(chǎn)生重要意義，但至今尚無(wú)這樣的標(biāo)志物為臨床所應(yīng)用。 雙鏈RNA-依賴的蛋白激酶（the double stranded RNA-dependentprotein kinase，PKR），是一種絲/蘇氨酸蛋白激酶，它是真核生物起始因子2α（eIF-2α）的特異蛋白激酶，雙鏈RNA可賦予或抑制其活性�；罨腜KR可形成同源二聚體，在多個(gè)絲/蘇氨酸殘基上實(shí)現(xiàn)自身磷酸化，然后催化其底物eIF-2α磷酸化，從而減少或抑制蛋白質(zhì)的合成和翻譯，在信號(hào)轉(zhuǎn)導(dǎo)、應(yīng)激、細(xì)胞生長(zhǎng)、分化和凋亡調(diào)控中起重要作用。PKR還可激活與炎癥、凋亡密切相關(guān)的NF-κB、P53等從而誘發(fā)炎癥反應(yīng)與腫瘤。幾乎所有細(xì)胞型中都有PKR基礎(chǔ)水平的表達(dá)，用干擾素誘導(dǎo)可以使其表達(dá)增高5~10倍。 目前，PKR被認(rèn)為是阿爾茨海默病調(diào)節(jié)的關(guān)鍵靶點(diǎn)，因此，研究其是否可作為與認(rèn)知功能減退相關(guān)的外周血生物學(xué)標(biāo)記具有可行性和必然性。 本課題以臨床患者為研究對(duì)象，對(duì)AD患者的外周血淋巴細(xì)胞中PKR的蛋白水平進(jìn)行研究，有助于臨床早期診斷和治療。 目的：1研究淋巴細(xì)胞中相關(guān)激酶PKR、P-PKR的表達(dá)情況，為篩查AD的可干預(yù)靶點(diǎn)提供細(xì)胞模型。 2在外周血淋巴細(xì)胞中研究細(xì)胞凋亡和細(xì)胞周期調(diào)控的相關(guān)激酶PKR、P-PKR的表達(dá)，尋找早期診斷AD的特異性外周標(biāo)記物。 3同時(shí)，對(duì)年齡相當(dāng)?shù)恼Ｈ�、輕度認(rèn)知功能障礙的患者以及同為神經(jīng)變性病的帕金森病患者外周血淋巴細(xì)胞中PKR、P-PKR水平進(jìn)行檢測(cè)，從而明確這一指標(biāo)的敏感性和特異性。 方法：1根據(jù)診斷標(biāo)準(zhǔn)和排除標(biāo)準(zhǔn)篩選病人，收集2010年9月至2011年10月河北醫(yī)科大學(xué)第二醫(yī)院神經(jīng)內(nèi)科門診的AD患者20例、MCI患者20例、PD患者20例、正常對(duì)照組20例，征得患者同意，利用簡(jiǎn)易精神狀態(tài)量表（MMSE）、臨床癡呆量表（CDR）等綜合評(píng)價(jià)認(rèn)知障礙的程度并記錄患者的個(gè)人信息。 2抽取患者新鮮靜脈血置于抗凝管中上下顛倒幾次，用人淋巴細(xì)胞分離液處理后經(jīng)離心洗滌提取外周血淋巴細(xì)胞。 3從外周血淋巴細(xì)胞中提取總蛋白，采用Western Blotting技術(shù)，分別檢測(cè)其中PKR、P-PKR的蛋白表達(dá)水平。 4統(tǒng)計(jì)學(xué)處理。采用SPSS17.0統(tǒng)計(jì)軟件包進(jìn)行處理。 結(jié)果：1AD患者外周血淋巴細(xì)胞中PKR、P-PKR水平較MCI組、PD組升高，較正常對(duì)照組顯著升高。 2MCI組、PD組外周血淋巴細(xì)胞中PKR、P-PKR水平相當(dāng)，較正常對(duì)照組升高，但升高幅度不明顯。 3外周血淋巴細(xì)胞中PKR、P-PKR水平與各組的MMSE評(píng)分、CDR評(píng)分呈負(fù)相關(guān)，與患者年齡和病程未見(jiàn)明顯相關(guān)。 結(jié)論：阿爾茨海默病早期往往無(wú)征兆，診斷困難。PKR、P-PKR在阿爾茨海默病患者、輕度認(rèn)知功能障礙患者、帕金森患者、正常對(duì)照組外周血淋巴細(xì)胞中均有表達(dá)，只是表達(dá)量有所不同，可以與其他標(biāo)志物一起聯(lián)合作為AD診斷的外周血標(biāo)志物。
[Abstract]:Alzheimer 's disease (AD), which is the most common type of senile dementia, is the most common type of senile dementia, which is characterized by cognitive impairment and behavioral impairment in the elderly and prophase. It is mainly manifested in progressive cognitive impairment. Mild cognitive dysfunction (Mild cognitive impa). Irment, MCI) is considered to be the preclinical of AD, which refers to the impairment of memory but has not reached the level of dementia. The population over 60 years old in China is 120 million, the prevalence rate of dementia is 3~8%, and more than 60% of them are Alzheimer's disease. In this proportion, there are an estimated 400~500 million AD in our country.
Parkinson's disease (Parkinson disease, PD), also known as shaking palsy (shaking palsy, paralysis agitans) is a kind of neurodegenerative disease common in the middle and old age. In 1817, the British doctor James Parkinson first described the onset age of.PD between the 40~70 years of age, among which the 50~60 year was the peak of the onset. China was 55 years old. The prevalence rate of the 65 year old group was about 1%, which was higher with age and slightly higher than that of the female.
With the aging process of the population, the incidence of Alzheimer's disease and Parkinson's disease has increased year by year. Especially, AD has become the fourth disease that leads to death after tumor, cardiovascular disease and cerebrovascular disease. The two all seriously affect the quality of life of the patients and bring heavy living and economic burden to the family, the government and the society.
The AD field at home and abroad is mostly about the damage of neurons after animal experiments or postmortem examination. It mainly discusses the internal relationship between the pathogenesis of AD and the mechanism of cell apoptosis and cell cycle disorders. However, early diagnosis of AD and the discovery of MCI patients are the basis for formulating therapeutic strategies and controlling the process of disease. Recent studies have shown that apoptosis and cell cycle in AD The dysregulation of phase regulation is not only limited to neurons, but also in peripheral blood lymphocytes and fibroblasts. Lymphocytes provide a convenient and useful model to study the role of cell cycle related events in the pathogenesis of AD and to find interferable targets.
Peripheral blood collection is convenient and peripheral blood lymphocytes (peripheral blood lymphocytes, PBLs) are lymphocytes in the blood circulation. It is mainly composed of T cells (about 70%~80%) and B cells (approximately 20%~30%). Therefore, in-depth study may provide a convenient and effective target for peripheral markers and drug intervention for early diagnosis of AD. If it can be from peripheral blood A simple and effective marker will be important for early diagnosis and treatment of AD. However, no such marker has been applied clinically.
Double stranded RNA- dependent protein kinase (the double stranded RNA-dependentprotein kinase, PKR), a kind of silk / threonine protein kinase, is a specific protein kinase of the eukaryotic initiation factor 2 alpha (eIF-2 a). Double stranded RNA can endow or inhibit its activity. Activated PKR can form homologous two polymer and can be realized on multiple silk / threonine residues. Body phosphorylation, then catalyzes the phosphorylation of its substrate eIF-2 a, thereby reducing or inhibiting the synthesis and translation of protein, and plays an important role in signal transduction, stress, cell growth, differentiation and apoptosis..PKR also activates NF- kappa B, which is closely related to apoptosis, and P53 induces inflammatory reactions and tumors. The expression of basal level of PKR can be increased by 5~10 times by interferon induction.
At present, PKR is considered to be the key target of Alzheimer's disease. Therefore, it is feasible and necessary to study whether it can be used as a biomarker of peripheral blood related to cognitive impairment.
This study is based on clinical patients. The study of PKR protein level in peripheral blood lymphocytes of AD patients is helpful for early diagnosis and treatment.
Objective: 1 to study the expression of PKR and P-PKR in lymphocytes, and provide a cell model for screening AD targets.
2 in peripheral blood lymphocytes, we studied the expression of PKR and P-PKR related to apoptosis and cell cycle regulation, looking for specific peripheral markers for early diagnosis of AD.
3 at the same time, PKR and P-PKR levels in peripheral blood lymphocytes of patients with normal age, mild cognitive impairment and the peripheral blood lymphocytes of Parkinson's disease with neurodegenerative disease were detected to determine the sensitivity and specificity of this index.
Methods: 1 according to the diagnostic criteria and exclusion criteria, 1 AD patients, 20 MCI patients, 20 PD patients and 20 normal controls were collected from September 2010 to October 2011 in the Department of Neurology in the Department of Neurology, Hebei Medical University. A comprehensive evaluation of the simple mental state scale (MMSE) and the Clinical Dementia Scale (CDR) was used. The degree of cognitive impairment was recorded and personal information was recorded.
2 the fresh venous blood of the patients was taken up and down several times in the anticoagulant tube. After treatment with human lymphocyte separation fluid, the peripheral blood lymphocytes were extracted by centrifugation.
3 the total protein was extracted from peripheral blood lymphocytes, and the protein expression level of PKR and P-PKR was detected by Western Blotting technique.
4 statistical processing. Use SPSS17.0 statistical software package for processing.
Results: the levels of PKR and P-PKR in peripheral blood lymphocytes of 1AD patients were higher than those in MCI group and PD group, which were significantly higher than those in normal control group.
In group 2MCI, the levels of PKR and P-PKR in peripheral blood lymphocytes of group PD were similar, higher than those of normal control group, but the amplitude of increase was not obvious.
3 the level of PKR and P-PKR in peripheral blood lymphocytes was negatively correlated with MMSE score and CDR score in each group, but no correlation was found between age and duration of disease.
Conclusion: Alzheimer's disease is often without signs and difficult to diagnose.PKR. P-PKR is expressed in the peripheral blood lymphocytes of Alzheimer's disease patients, mild cognitive impairment patients, Parkinson patients and normal control group, but the expression amount is different, which can be combined with other markers as the peripheral blood markers for the diagnosis of AD.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.1

【參考文獻(xiàn)】

相關(guān)期刊論文 前4條

1 王洪權(quán);胡海濤;;阿爾茨海默病中鈣調(diào)節(jié)障礙[J];國(guó)外醫(yī)學(xué)(醫(yī)學(xué)地理分冊(cè));2008年01期

2 鄭妍鵬;何金生;洪濤;;阿爾茨海默病體液生物學(xué)標(biāo)記物研究進(jìn)展[J];中國(guó)科學(xué)(C輯:生命科學(xué));2009年09期

3 任惠民;;蛋白質(zhì)氧化與阿爾茨海默病[J];中國(guó)臨床神經(jīng)科學(xué);2010年04期

4 樂(lè)衛(wèi)東;陳晟;;阿爾茨海默病生物學(xué)標(biāo)記和早期診斷研究進(jìn)展[J];老年醫(yī)學(xué)與保健;2005年04期

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