本文選題：高膽固醇 + 認知功能障礙�。� 參考：《第三軍醫(yī)大學》2017年碩士論文

【摘要】：研究背景認知功能障礙包括輕度認知損害(MCI)和癡呆,在老年人群發(fā)生率較高,預計到2050年全球認知功能障礙患者將遠超1.5億。認知功能障礙可顯著影響患者本人生活質(zhì)量,大量認知功能障礙患者給其家庭同時給社會都帶來了破壞性的影響。目前關(guān)于認知功能障礙尚無有效的治療方法,對其進行一級預防尤為重要。探索認知功能障礙發(fā)生的危險因素及發(fā)生的機制能夠為其防治提供重要的理論依據(jù)。國內(nèi)外大量研究表明高血壓、糖尿病等血管危險因素可以增加認知功能障礙的風險。然而,關(guān)于高膽固醇與認知功能障礙之間關(guān)系的前瞻性研究較少,相關(guān)機制尚不清楚,并且未得出一致的結(jié)論。有研究認為高膽固醇血癥可增加阿爾茨海默病(AD)和血管性癡呆(VD)的認知功能損害程度,但也有學者認為血漿膽固醇水平降低可以加劇認知功能的減退。因此,高膽固醇血癥是否增加認知功能障礙的風險尚有較大爭議。AD是認知功能障礙中最常見的疾病。在動物模型中已經(jīng)證明高膽固醇可以增加腦內(nèi)β淀粉樣蛋白(Aβ)的含量,促進腦內(nèi)Ab的積聚,與AD老年斑的形成密切相關(guān),但高膽固醇導致腦內(nèi)Ab積聚的機制仍不清楚。Science上發(fā)表的一篇研究認為Aβ在腦內(nèi)清除轉(zhuǎn)運的平衡機制可能也參與了腦內(nèi)Ab的積聚過程。高膽固醇是否會通過影響Aβ跨血腦屏障的轉(zhuǎn)運進而導致腦內(nèi)Ab積聚尚不清楚。闡明高膽固醇對Aβ跨血腦屏障轉(zhuǎn)運機制的影響,對于進一步探索高膽固醇導致認知功能障礙發(fā)生的機制具有重要意義。本研究將從臨床和基礎兩個方面進行研究。第一部分為臨床研究,探討高膽固醇血癥與認知功能障礙的關(guān)系及對Aβ代謝的影響;第二部分為實驗研究,通過腦微血管內(nèi)皮細胞Aβ轉(zhuǎn)運受體的表達,探討高膽固醇對Aβ代謝的影響。第一部分高膽固醇對認知功能障礙及Aβ代謝影響的臨床研究目的:在60歲以上的老年人群中,探討高膽固醇血癥與認知功能障礙發(fā)生的關(guān)系,以及認知功能障礙發(fā)生中高膽固醇對血清Aβ水平的影響,為認知功能障礙的防治提供臨床依據(jù)。方法:收集2015年3月至2015年12月于我科住院無認知功能障礙的患者,進行1年的隨訪。入組時收集血脂指標及他汀類藥物使用情況,通過簡易精神狀態(tài)量表(MMSE)評估其認知功能。根據(jù)末次隨訪時MMSE評分分為認知功能正常組及認知功能障礙組。隨機抽取高膽固醇血癥和無高膽固醇血癥患者各20例,末次隨訪時收集血液標本通過ELISA試劑盒檢測血清Aβ1-40及Aβ1-42水平。分析高膽固醇血癥及他汀類藥物治療與認知功能障礙的關(guān)系,并分析高膽固醇血癥對血清Aβ水平的影響。結(jié)果:1.基線共納入388例患者,平均年齡為71.27±8.042歲,其中男性202例(52.1%),女性186例(47.9%)。384例(99.0%)患者完成1年的隨訪,其中高膽固醇血癥患者177例(46.1%),認知功能障礙患者62例(16.1%)。2.認知功能障礙組與認知功能正常組相比,患者年齡較大;男性比例較高;高血壓、糖尿病及高膽固醇血癥患者比例較高;腦白質(zhì)病變(WML)分值、血清低密度脂蛋白膽固醇(LDL-C)及糖化血紅蛋白(HbA1c)水平較高;使用他汀類藥物的患者比例較低,以上差異均具有統(tǒng)計學意義(P0.05)。3.高膽固醇血癥患者血清Aβ1-40水平及血清Aβ1-42水平均顯著低于無高膽固醇血癥患者(P(27)0.05)。4.認知功能各個方面中,高膽固醇血癥患者基線視空間與執(zhí)行功能、注意力及計算力、語言及抽象能力等認知功能分值均顯著低于無高膽固醇血癥患者(P0.05),但高膽固醇血癥組僅視空間及執(zhí)行功能1年內(nèi)下降分值顯著高于無高膽固醇血癥組(P0.05)。5.調(diào)整了年齡、性別、高血壓、糖尿病、Hb A1c及WML等因素的影響后,二分類logistic回歸顯示,高膽固醇血癥(OR:3.013,95%CI:1.628-5.164,P(27)0.05)及血清LDL-C水平(OR:1.676,95%CI:1.200-2.222,P(27)0.05)與認知功能障礙的發(fā)生密切相關(guān),而他汀藥物使用(OR:0.799,95%CI:0.361-0.974,P(27)0.05)與認知功能障礙呈負相關(guān)。結(jié)論:1.高膽固醇血癥尤其血清LDL-C水平增高可以增加認知功能障礙發(fā)生的風險。2.高膽固醇血癥組血清Aβ水平低于無高膽固醇血癥組。3.高膽固醇血癥與認知功能障礙中執(zhí)行功能減退密切相關(guān)。4.他汀類藥物的使用可以降低認知功能障礙發(fā)生的風險。第二部分高膽固醇對Aβ代謝影響的實驗研究目的:探索高膽固醇對小鼠腦微血管內(nèi)皮細胞Aβ轉(zhuǎn)運受體LRP-1和RAGE表達的影響,為研究高膽固醇導致認知功能障礙發(fā)生的機制提供實驗依據(jù)。方法:分離培養(yǎng)年輕小鼠(C57BL/6,6-8周齡)及老年鼠(C57BL/6,12月齡)腦微血管內(nèi)皮細胞,分別進行正常培養(yǎng)(正常小鼠組、正常老年鼠組)和高膽固醇處理培養(yǎng)(高膽固醇小鼠組、高膽固醇老年鼠組),通過QPCR法和Western Blot法分別檢測各組LRP-1及RAGE mRNA和蛋白的表達。結(jié)果:1.正常小鼠組、正常老年鼠組、高膽固醇小鼠組及高膽固醇老年鼠組LRP-1mRNA(F=64.317,P(27)0.001)及蛋白(F=522.205,P(27)0.001)表達呈遞減趨勢。各組間兩兩比較,正常老年鼠組、高膽固醇小鼠組及高膽固醇老年鼠組LRP-1 mRNA(P(27)0.05)及蛋白(P(27)0.001)表達量均明顯低于正常小鼠組,高膽固醇小鼠組及高膽固醇老年鼠組LRP-1 m RNA及蛋白表達量與正常老年鼠相比,均顯著下降(P(27)0.05),高膽固醇老年鼠組LRP-1 m RNA及蛋白表達量低于高膽固醇小鼠組,差異有統(tǒng)計學意義(P(27)0.05)。2.正常小鼠組、正常老年鼠組、高膽固醇小鼠組及高膽固醇老年鼠組RAGE mRNA(F=146.999,P(27)0.001)及蛋白(F=879.362,P(27)0.001)表達呈遞增趨勢。各組間兩兩比較,正常老年鼠組、高膽固醇小鼠組及高膽固醇老年鼠組RAGE m RNA(P(27)0.05)及蛋白(P(27)0.001)表達量均明顯高于正常小鼠組,高膽固醇小鼠組及高膽固醇老年鼠組RAGE m RNA(P(27)0.001)及蛋白(P(27)0.05)表達量與正常老年鼠相比,均顯著增高,高膽固醇老年鼠組RAGE m RNA(P(27)0.001))及蛋白(P(27)0.05)表達量高于高膽固醇小鼠組,差異有統(tǒng)計學意義。結(jié)論:在高膽固醇狀態(tài)下,小鼠腦微血管內(nèi)皮細胞LRP-1表達量下降,RAGE表達量增高,提示高膽固醇通過影響Aβ轉(zhuǎn)運蛋白,進而影響Aβ的轉(zhuǎn)運清除,增加認知功能損害的風險。
[Abstract]:Backgroundcognitive dysfunction including mild cognitive impairment (MCI) and dementia in the elderly population, high incidence rate, is expected to 2050 global cognitive dysfunction will be far more than 150 million. Cognitive dysfunction can significantly affect the quality of life of the patient, a large number of patients with cognitive impairment to their families and society to have devastating effects on the treatment. There is no effective method for cognitive dysfunction, for the primary prevention of the particularly important. To explore the risk factors of cognitive dysfunction and the mechanism can provide important theoretical basis for its prevention and treatment. A large number of domestic and foreign research shows that hypertension, vascular risk factors such as diabetes can increase the risk of cognitive impairment. However, prospective studies on the relationship between high cholesterol and cognitive dysfunction is less, related mechanism is not clear, and did not come to the same Conclusion. Studies have suggested that high cholesterol can increase Alzheimer's disease (AD) and vascular dementia (VD) and the degree of cognitive impairment, but also some scholars believe that the reduction of plasma cholesterol levels decline may enhance cognitive function. Therefore, whether hypercholesterolemia increases the risk of cognitive dysfunction is still controversial.AD is the most common disease. Cognitive dysfunction in animal models has shown that high cholesterol can increase brain amyloid beta (A beta) content, promote the accumulation of Ab in the brain, and is closely related to the formation of AD plaque, but the mechanisms leading to high cholesterol in the brain of Ab accumulation is still not clear in a study published in the.Science. Think of A beta in the brain to clear the balance mechanism of transport may also be involved in the accumulation of Ab in the brain. Whether high cholesterol will be influenced by the beta A cross the blood-brain barrier and brain Ab accumulated in transport It is unclear. To clarify the effects of high cholesterol on A beta across the blood brain barrier transporter mechanism, to further explore the mechanism of cognitive dysfunction associated with high cholesterol has important significance. This research will study from two aspects. The first part is the basis of clinical and clinical research, explore the hypercholesterolemia and cognitive dysfunction and effect of A beta metabolism; the second part is the experimental research, through the expression of brain microvascular endothelial cells A beta transport receptor, to investigate the effects of high cholesterol on A beta metabolism. Objective to evaluate the clinical results of the first part of high cholesterol on cognitive dysfunction and metabolic effects of A beta: Elderly people over the age of 60, to explore the relationship between high cholesterol and cognitive dysfunction, and cognitive dysfunction in high cholesterol effect on serum A, for the prevention and treatment of cognitive dysfunction in clinical According to. Methods: from March 2015 to December 2015 in our hospital without cognitive impairment patients, followed up for 1 years. When the group collected blood fat index and statin use by mini mental state examination (MMSE) to assess the cognitive function. According to the MMSE scores were divided into normal cognitive function group and cognitive dysfunction group randomly. Hypercholesterolemia and hypercholesterolemia were 20 cases each, at the end of the follow-up blood samples collected by serum A detection kit 1-40 beta ELISA and A beta 1-42. Analysis of the relationship between high cholesterol and statins therapy and cognitive dysfunction, and analyze the effect of hypercholesterolemia the serum A. Results: 1. baseline included 388 patients with an average age of 71.27 + 8.042 years, including 202 cases of male female 186 cases (52.1%), (47.9%).384 cases (99%) patients completed 1 years with Visit, including 177 cases of patients with hypercholesterolemia (46.1%), 62 cases of patients with cognitive impairment (16.1%) compared to the.2. cognitive dysfunction group and cognitive function in the normal group, the patients were older; the higher proportion of males; hypertension, diabetes and hypercholesterolemia, a higher proportion of patients; cerebral white matter lesions (WML) score, serum low density lipoprotein protein cholesterol (LDL-C) and glycosylated hemoglobin (HbA1c) level is higher; the use of statins in patients with a lower proportion, the above differences were statistically significant (P0.05 1-40) level and serum A beta.3. hypercholesterolemia serum A beta 1-42 levels were significantly lower than non patients with hypercholesterolemia (P (27) 0.05) the cognitive function of.4. in patients with hypercholesterolemia, baseline visual spatial and executive function, attention and computing power, language ability and abstract cognitive function scores were significantly lower than non patients with hypercholesterolemia (P0.05 ), but high cholesterol group only visual spatial and executive function within 1 years of decline were significantly higher than those without hypercholesterolemia group (P0.05.5.) adjusted for age, sex, hypertension, diabetes mellitus, and the effect of Hb A1c WML and other factors, two classification logistic regression showed that hypercholesterolemia (OR:3.013,95%CI:1.628-5.164, P (27) 0.05) and the serum level of LDL-C (OR:1.676,95%CI:1.200-2.222, P (27) 0.05) closely associated with cognitive dysfunction, and statin use (OR:0.799,95%CI:0.361-0.974, P (27) 0.05) was negatively correlated with cognitive impairment. Conclusions: 1. hypercholesterolemia especially elevated serum LDL-C level can increase the incidence of cognitive dysfunction the risk of.2. hypercholesterolemia serum beta A level is lower than the executive function without hypercholesterolemia group.3. hypercholesterolemia and cognitive dysfunction in hypothyroidism is closely related to.4. use of statins You can reduce the risk of cognitive dysfunction. Objective to study on effect of second high cholesterol on A beta metabolism: To explore the effects of high cholesterol on mice brain microvascular endothelial cells A beta transport receptor LRP-1 and RAGE expression, and provide experimental basis for the study of mechanism of cognitive dysfunction associated with high cholesterol. Methods: cultured young mice (C57BL/6,6-8 weeks old) and aged rats (C57BL/6,12 months) of brain microvascular endothelial cells were cultured in normal (normal mice group, normal rats group) and high cholesterol treatment (Gao Dan sterol mice group, high cholesterol group of aged rats), the expression levels of LRP-1 and RAGE mRNA and protein were detected by QPCR method the Western and Blot method. Results: 1. normal mice group, normal rats group, high cholesterol group and high cholesterol mouse aged rats group LRP-1mRNA (F=64.317, P (27) and protein (F=522.20 0.001) 5,P(27)0.001)琛ㄨ揪鍛堥，

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