本文選題：輕度認(rèn)知功能障礙 + 認(rèn)知減退�。� 參考：《山西醫(yī)科大學(xué)》2009年博士論文

【摘要】： 研究背景: 隨著世界人口老齡化發(fā)展,癡呆正在成為一個(gè)全球性公共衛(wèi)生問(wèn)題。輕度認(rèn)知功能障礙(MCI)是介于正常老化和癡呆或阿爾茲海默病(AD)之間過(guò)渡階段,處于此階段個(gè)體存在超出其年齡范圍的記憶或其它認(rèn)知障礙,但仍能維持功能完好,且達(dá)不到癡呆的診斷標(biāo)準(zhǔn)。研究MCI的人群分布特征和轉(zhuǎn)歸影響因素對(duì)于實(shí)現(xiàn)癡呆的早期防治和臨床前預(yù)警有重要價(jià)值。 目的 1.了解太原市城區(qū)65歲以上老年人輕度認(rèn)知障礙的現(xiàn)患率及人群分布特征。 2.探明不同人口學(xué)特征、疾病史、遺傳特征人群(不同ApoEε4)及人格特征人群(依據(jù)16種基本人格與4個(gè)次元因素)MCI轉(zhuǎn)歸結(jié)果及影響因素的差異。 3.探明全血APP基因、血脂及ApoEε4在由MCI發(fā)展為癡呆中獨(dú)立作用、相互關(guān)系和聯(lián)合作用。 4.探明老年癡呆早期認(rèn)知功能障礙的特點(diǎn),在MCI階段中哪些指標(biāo)是老年癡呆的危險(xiǎn)信號(hào)? 5.提出判定發(fā)展為老年性癡呆敏感、特異、廉價(jià)、實(shí)用的檢測(cè)手段及指標(biāo)。 對(duì)象和方法 本研究采用傳統(tǒng)、規(guī)范流行病學(xué)設(shè)計(jì)方案,分為現(xiàn)況研究、病例對(duì)照研究、巢氏病例對(duì)照研究和隊(duì)列研究四個(gè)部分。 1.研究對(duì)象 在太原市范圍內(nèi),采用整群隨機(jī)抽樣方法調(diào)查社區(qū)65歲以上老年人6192人,在基底人群中篩選600 MCI對(duì)象構(gòu)成隊(duì)列人群,按半年一次隨訪計(jì)劃,完成三次隨訪。 2.研究方法 ①基線調(diào)查 對(duì)符合納入標(biāo)準(zhǔn)的6192名老年人進(jìn)行集中和入戶調(diào)查,MCI診斷標(biāo)準(zhǔn)參考DSM-IV“輕微神經(jīng)認(rèn)知障礙”,采用MMSE、GDS、ADL,對(duì)研究人群進(jìn)行認(rèn)知功能評(píng)定,可疑MCI及老年癡呆患者由神經(jīng)科醫(yī)師進(jìn)一步做出診斷,排除特定原因引起的MCI,從中篩查MCI者600人。 ②病例對(duì)照研究 病例和對(duì)照采用n:m不等比匹配方法進(jìn)行選取,按照前述標(biāo)準(zhǔn)入選患MCI者423人。對(duì)照年齡與病例年齡在±2歲,性別相同,文化程度一致,無(wú)嚴(yán)重軀體疾病能完成神經(jīng)心理測(cè)驗(yàn),上述記憶、認(rèn)知等檢查均正常,最終入選995人。應(yīng)用cox回歸模型進(jìn)行不等比匹配Logistic回歸分析,分析社會(huì)人口學(xué)、生活方式、疾病史、人格特征、生理、血清生化及基因型別指標(biāo)對(duì)MCI發(fā)生的影響作用。 ③巢氏病例對(duì)照研究 由600名患輕度認(rèn)知功能損害的社區(qū)老年居民組成隨訪隊(duì)列,與基線調(diào)查相比,智商降低1個(gè)SD被認(rèn)為認(rèn)知減退,按年齡、性別、文化程度1:1匹配后形成認(rèn)知減退組和對(duì)照組后進(jìn)行影響因素分析。 ④隊(duì)列研究 篩選600 MCI對(duì)象構(gòu)成隊(duì)列人群,按半年一次隨訪預(yù)定計(jì)劃,分別于2007年11月、2008年6月、2008年12月完成三次隨訪。中文版MMSE、GDS、ADL、WAIS-RC比較MCI和認(rèn)知正常受試者轉(zhuǎn)化為癡呆、AD或VD的年轉(zhuǎn)化率。采用cox回歸模型分析上述基線指標(biāo)(一般人口學(xué)特征、疾病史、基因標(biāo)記、人格特征、血清生化指標(biāo))對(duì)MCI者發(fā)生認(rèn)知減退轉(zhuǎn)化的預(yù)測(cè)價(jià)值。 ⑤實(shí)驗(yàn)室檢查 對(duì)全部MCI和老年癡呆患者抽取靜脈血,檢測(cè)血中ApoEε4、全血APP基因表達(dá)、血脂系列。所有指標(biāo)均設(shè)正常對(duì)照進(jìn)行群組比較研究。對(duì)所有MCI和老年癡呆患者采用16PF測(cè)定人格,同時(shí)采用韋氏成人智力量表(WAIS-RC)進(jìn)行智商評(píng)估。 ⑥統(tǒng)計(jì)分析 EpiDate3.0軟件建立數(shù)據(jù)庫(kù)進(jìn)行兩次數(shù)據(jù)錄入。采用SPSS13.0軟件進(jìn)行分析,首先進(jìn)行單因素分析,在此基礎(chǔ)上結(jié)合專業(yè)知識(shí),用多因素分析方法對(duì)某些可能引起混雜作用變量進(jìn)行調(diào)整。多因素分析采用1:1匹配Logistic回歸模型及n:m不等比匹配Logistic回歸模型分析。隨訪資料按照人年法計(jì)算發(fā)病密度及比較轉(zhuǎn)化為認(rèn)知減退RR和95 %CI ;采用Log-rank檢驗(yàn)對(duì)每一指標(biāo)不同水平隨訪對(duì)象認(rèn)知減退轉(zhuǎn)歸比較。所有統(tǒng)計(jì)檢驗(yàn)均為雙側(cè)檢驗(yàn)。轉(zhuǎn)歸影響因素篩選若是不可控制變量采用Cox Regression過(guò)程,可控制變量采用Cox w/Time-Dep Cov過(guò)程完成。 結(jié)果 1.現(xiàn)況研究MCI人群發(fā)生率9.70% (95% CI: 9.62%- 9.77%),單因素結(jié)果顯示年齡、性別、文化程度、月經(jīng)濟(jì)收入和婚姻狀況( p 0.01),但與職業(yè)無(wú)關(guān)( P 0.05)。多因素Logistic回歸分析結(jié)果顯示:年齡、性別、文化程度、婚姻狀況和職業(yè)、年齡和性別交互作用具有顯著統(tǒng)計(jì)學(xué)意義( p 0.05)。 2.病例對(duì)照研究 最終入選病例423人,對(duì)照925人。通過(guò)單因素和多因素cox回歸分析,得出MCI發(fā)生危險(xiǎn)因素,其OR值及95%CI分別是:從事體力勞動(dòng):1.396(1.092-1.785);吸煙:1.551(1.021-2.359);血清中較高血糖濃度:1.354(1.102-1.664);較高高密度脂蛋白水平:1.543(1.232-1.932);較高低密度脂蛋白水平:1.299(1.060-1.592);低雌激素水平:1.263(1.031-1.547);高血壓:1.967(1.438-2.689);糖尿病:1.381(1.139-1.675);抑郁癥:1.406(1.110-1.780);腦血栓:1.593(1.307-1.943);較高收縮壓:1.331(1.129-1.569);ApoEε4型等位基因:1.462(1.140-1.873);保護(hù)因素有:常讀書(shū)看報(bào):0.610(0.503-0.740);常參加公益活動(dòng):0.617(0.502-0.757);常做家務(wù):0.804(0.665-0.973);退休后有第二職業(yè):0.759(0.636-0.906);嗅覺(jué)敏銳:0.900(0.845-0.958);外向人格:0.829(0.699-0.984);果斷人格:0.811(0.662-0.993)。 3.巢氏病例對(duì)照研究 危險(xiǎn)因素有從事體力勞動(dòng)(OR:1.9,95%CI:1.0-3.6)、吸煙(OR:2.1,95%CI:1.0-4.4)、喜歡呆在家里(OR:2.3,95%CI:1.0-4.9)、血清中較高血糖(OR:3.6,95%CI:1.9-6.8)、膽固醇(OR:2.2,95%CI:1.1-4.3)、低雌激素水平(OR:1.9,95%CI:1.1-3.4),高血壓(OR:4.0,95%CI:1.8-4.6),糖尿病(OR:3.0,95%CI:1.9-4.2),高血脂(OR:4.1,95%CI:1.7-9.6),腦血栓(OR:2.3,95%CI:1.3-4.5),腦出血(OR: 2.7,95%CI:1.6-4.8),較高收縮壓(OR:2.2,95%CI:1.3-3.6),ApoEε4型等位基因(OR:2.7,95%CI:1.1-6.7)、ApoEε4型等位基因*膽固醇(OR:1.6,95%CI:1.0-2.6);保護(hù)因素有:常讀書(shū)看報(bào)(OR:0.2,95%CI: 0.1-0.4)、常做家務(wù)(OR:0.2,95%CI:0.1-0.5)、外向人格(OR: 0.5,95%CI: 0.3-0.9)。 4.隊(duì)列研究 112對(duì)認(rèn)知減退和正常對(duì)照納入研究,認(rèn)知減退組人年發(fā)病密度14.70%(14.52%,15.29%)和正常對(duì)照組3.75%(3.56%,3.67%)兩組隨訪對(duì)象轉(zhuǎn)化為認(rèn)知減退結(jié)局的生存曲線經(jīng)Log-rank檢驗(yàn)差異有統(tǒng)計(jì)學(xué)意義(χ2=11.643,P 0.01) ,600隨訪對(duì)象,最終557人納入研究,三年隨訪后人年發(fā)病密度15.31%(13.99%,16.87%)。采用cox回歸模型進(jìn)行單因素及多因素分析結(jié)果顯示:MCI發(fā)生認(rèn)知減退轉(zhuǎn)歸結(jié)局因素如下:年齡(RR:1.957;95%CI:1.916-1.999)、女性(RR:2.713;95%CI:1.616-4.554)、高文化程度(RR:0.662;95%CI:0.500-0.877)、糖尿病(RR:2.890;95%CI:1.635-5.107)、腦血栓(RR:1.898;95%CI: 1.157-3.114)、ApoEε4攜帶者(RR:1.876;95%CI: 1.139-3.090)、內(nèi)向人格(RR:1.876;95%CI:1.139-3.090)、焦慮人格(RR:2.515;95%CI:1.342-4.711)、高血糖(RR:1.3236;95%CI: 1.193-1.470)、高膽固醇(RR:2.390;95%CI:1.288-4.436)。 結(jié)論 1.社區(qū)65歲以上老年人群存在較高M(jìn)CI發(fā)生率,此部分人群作為老年癡呆的高危人群給予足夠關(guān)注,加強(qiáng)防范。 2.MCI是介于認(rèn)知正常和認(rèn)知減退之間的一種過(guò)渡階段的認(rèn)知障礙,MCI轉(zhuǎn)化為認(rèn)知減退結(jié)局的危險(xiǎn)性遠(yuǎn)遠(yuǎn)大于認(rèn)知正常受試者。 3.橫斷面研究顯示:人口學(xué)特征中高齡、老年女性、較低文化程度、體力勞動(dòng)、獨(dú)身是MCI發(fā)生的危險(xiǎn)因素。年齡與性別存在明顯交互作用,提示高齡女性是MCI發(fā)生的高危人群,應(yīng)引起重視。 4.回顧性研究顯示:體力勞動(dòng)、不健康生活方式、罹患糖尿病、高血壓、高血糖、高血脂、抑郁癥、腦血管病變發(fā)生風(fēng)險(xiǎn)是老年人MCI發(fā)生的可疑危險(xiǎn)因素,嗅覺(jué)減退、內(nèi)向人格、攜帶ApoEε4型等位基因可作為預(yù)示MCI發(fā)生的早期指征,ApoEε4基因型和LDL存在交互作用。 5.前瞻性研究顯示:人口學(xué)特征(高齡、女性、較低文化程度)、疾病史(罹患糖尿病和腦出血)、ApoEε4基因型攜帶者、血清較高血糖、膽固醇及低密度脂蛋白及內(nèi)向、焦慮人格特征是影響轉(zhuǎn)歸危險(xiǎn)因素,堅(jiān)持腦力勞動(dòng)、健康生活方式、降低糖尿病、高血壓、高血糖、高血脂、腦血管病變發(fā)生風(fēng)險(xiǎn)是預(yù)防老年人認(rèn)知減退主要手段,內(nèi)向人格、攜帶ApoEε4型等位基因可作為預(yù)示認(rèn)知減退的早期指征。 6.通過(guò)對(duì)社區(qū)老年人群輕度認(rèn)知功能障礙發(fā)生的影響因素與認(rèn)知減退轉(zhuǎn)歸的影響因素的對(duì)比,發(fā)現(xiàn)具有較高的一致性,提示對(duì)社區(qū)MCI人群早期干預(yù)可能對(duì)認(rèn)知減退甚至老年癡呆預(yù)防起到重要作用。
[Abstract]:Research background:
With the aging of the world's population, dementia is becoming a global public health problem. Mild cognitive dysfunction (MCI) is a transitional stage between normal aging and dementia or Alzheimer's disease (AD). At this stage, the individual has memory or other cognitive impairments beyond its age, but it still maintains functional integrity, and The diagnostic criteria of dementia can not be reached. It is of great value to study the distribution characteristics and the influencing factors of MCI in the early prevention and pre-warning of dementia.
objective
1. to understand the prevalence rate and distribution characteristics of mild cognitive impairment among the elderly over 65 years old in Taiyuan city.
2. the results of different demographic characteristics, disease history, hereditary population (different ApoE E 4) and personality traits (according to 16 basic personality and 4 dimensional factors) and the difference of influencing factors were identified.
3. it is proved that the whole blood APP gene, blood lipid and ApoE E 4 play an independent role in the development of MCI from dementia to dementia.
4. to identify the characteristics of early cognitive impairment in Alzheimer's disease. What indicators are the risk signals for Alzheimer's disease in the MCI stage?
5., we propose to develop sensitive, specific, inexpensive and practical detection methods and indicators for Alzheimer's disease.
Objects and methods
This study used traditional and standardized epidemiological design programs, which were divided into four parts: current research, case-control study, nested case-control study and cohort study.
1. research objects
In the Taiyuan City, a cluster random sampling method was used to investigate 6192 elderly people over 65 years old in the community, and 600 MCI objects were selected from the base population to form a cohort, and three follow-up was completed according to a half year follow-up plan.
2. research methods
Baseline survey
A survey was conducted on 6192 elderly people conforming to the inclusion criteria. The MCI diagnostic criteria referred to DSM-IV "mild neurocognitive impairment", using MMSE, GDS, and ADL to assess the cognitive function of the study population. The suspected MCI and Alzheimer's patients were further diagnosed by neurologist, excluding specific causes of MCI, and screened M from them. The CI was 600.
A case-control study
The cases and the controls were selected by the n:m unequal matching method, and 423 people with MCI were selected according to the previous standard. The age and age of the cases were at the age of + 2. The sex was the same, the cultural degree was the same, no serious physical disease could complete the neuropsychological test. The above memory and cognition were all normal, and 995 people were finally selected. The Cox regression model was used. Logistic regression analysis was used to analyze the effects of social demography, lifestyle, disease history, personality, physiology, serum biochemical and genotypic indicators on the occurrence of MCI.
A case-control study of nests
600 elderly residents with mild cognitive impairment were followed up in a follow-up cohort. Compared with the baseline survey, the decrease of IQ of 1 SD was considered to be cognitive impairment, and the influence factors were analyzed after the age, gender, and educational level of 1:1 matched the cognitive impairment group and the control group.
Cohort study
A cohort of 600 MCI was selected to form a cohort and three follow-up visits were completed in November 2007, June 2008, and December 2008 respectively. The Chinese version of MMSE, GDS, ADL, WAIS-RC, MCI and cognitive normal subjects were transformed into dementia, AD or VD's annual conversion rate. The above baseline indicators were analyzed by the Cox regression model (general Demography). Characteristics, disease history, genetic markers, personality characteristics and serum biochemical markers were predictive values of cognitive decline in MCI patients.
Laboratory examination
The venous blood was extracted from all MCI and Alzheimer's patients. The blood ApoE E 4, the whole blood APP gene expression and the blood lipid series were measured. All the indexes were compared with the normal control group. All MCI and Alzheimer's patients were determined by 16PF, and the Wechsler Adult Intelligence Scale (WAIS-RC) was used to evaluate the IQ.
Statistical analysis
The EpiDate3.0 software establishes the database for two data entry. The SPSS13.0 software is used to analyze the data. First, the single factor analysis is carried out. On this basis, a combination of professional knowledge and multi factor analysis method is used to adjust some possible mixed variables. The multi factor analysis adopts the 1:1 matching Logistic regression model and the n:m unequal ratio matching L. Ogistic regression model analysis. The follow-up data were calculated according to the human year method and converted to cognitive impairment RR and 95%CI. Log-rank test was used to compare the cognitive impairment of the follow-up subjects at the different levels of each index. All the statistical tests were both bilateral tests. If the factors were not controlled by Cox Regres, the influence factors were selected. The sion process can be controlled by Cox w/Time-Dep Cov process.
Result
1. the prevalence of MCI was 9.70% (95% CI: 9.62%- 9.77%). Single factor results showed age, sex, education, monthly economic income and marital status (P 0.01), but not related to occupation (P 0.05). The results of multiple factor Logistic regression analysis showed age, sex, marital status and occupation, age and sex interaction. There was significant statistical significance (P 0.05).
2. case control study
423 people were selected and 925 people were selected as control. By single factor and multiple factor Cox regression analysis, the risk factors of MCI were found. The OR value and 95%CI were 1.396 (1.092-1.785); smoking: 1.551 (1.021-2.359); high blood glucose concentration in the serum, 1.354 (1.102-1.664); higher HDL level: 1.543 (1.232-1.932); compared with high density lipoprotein (1.232-1.932); High and low density lipoprotein levels: 1.299 (1.060-1.592); low estrogen level: 1.263 (1.031-1.547); hypertension: 1.967 (1.438-2.689); diabetes: 1.381 (1.139-1.675); depression: 1.406 (1.110-1.780); cerebral thrombosis: 1.593 (1.307-1.943); higher systolic pressure: 1.331 (1.129-1.569); ApoE E 4); 1.462 (1.140-1.873); protective factors: often Reading and reading newspapers: 0.610 (0.503-0.740); often participating in public welfare activities: 0.617 (0.502-0.757); often doing housework: 0.804 (0.665-0.973); after retirement there are second occupations: 0.759 (0.636-0.906); acute smell: 0.900 (0.845-0.958); extrovert personality 0.829 (0.699-0.984); decisive personality: 0.811 (0.662-0.993).
3. nests case control study
Risk factors include OR:1.9,95%CI:1.0-3.6, OR:2.1,95%CI:1.0-4.4, OR:2.3,95%CI:1.0-4.9, high blood sugar (OR:3.6,95%CI:1.9-6.8), cholesterol (OR:2.2,95%CI:1.1-4.3), low estrogen (OR:1.9,95%CI:1.1-3.4), OR:4.0,95%CI:1.8-4.6, and diabetes (OR:3.0,95%CI:1). .9-4.2), hyperlipidemia (OR:4.1,95%CI:1.7-9.6), cerebral thrombosis (OR:2.3,95%CI:1.3-4.5), cerebral hemorrhage (OR: 2.7,95%CI:1.6-4.8), higher systolic pressure (OR:2.2,95%CI:1.3-3.6), ApoE epsilon 4 allele (OR:2.7,95%CI:1.1-6.7) and ApoE - 4 allele * cholesterol (OR:1.6,95%CI:1.0-2.6); protective factors are: reading newspapers (OR:0.2,95%CI: 0.1-0.4), I often do housework (OR:0.2,95%CI:0.1-0.5) and OR: 0.5,95%CI: 0.3-0.9.
4. cohort study
112 of cognitive hypogonties and normal controls were included in the study. The annual density of the cognitive impairment group was 14.70% (14.52%, 15.29%) and 3.75% (3.56%, 3.67%) in the normal control group (3.56%, 3.67%). The survival curves converted to cognitive decline were statistically significant (x 2=11.643, P 0.01), 600 follow-up subjects, and 557 were finally included in the study. The annual incidence of the three year follow-up was 15.31% (13.99%, 16.87%). The results of single factor and multi factor analysis by Cox regression model showed that the factors of cognitive impairment outcome in MCI were as follows: age (RR:1.957; 95%CI:1.916-1.999), women (RR:2.713; 95%CI: 1.616-4.554), high education (RR:0.662; 95%CI:0.500-0.877), and diabetes mellitus (RR:2.8). 90; 95%CI:1.635-5.107), brain thrombus (RR:1.898; 95%CI: 1.157-3.114), ApoE epsilon 4 carrier (RR:1.876; 95%CI: 1.139-3.090), introverted personality (RR:1.876; 95%CI:1.139-3.090), anxiety personality (RR:2.515; 95%CI:1.342-4.711), hyperglycemia, high cholesterol (95%), high cholesterol.
conclusion
1. there is a high incidence of MCI in the community over 65 years old. This group of people as a high-risk group of Alzheimer's disease should pay enough attention to strengthen prevention.
2.MCI is a cognitive disorder in the transitional stage between cognitive normal and cognitive impairment, and the risk of transforming MCI into cognitive impairment is far greater than that of cognitive subjects.
3. the cross-sectional study shows that age and sex are the risk factors for MCI in the age of demographics, older women, lower cultural level, physical labor and single body. Age and sex have obvious interaction, suggesting that older women are high-risk groups of MCI and should be paid attention to.
4. retrospective studies have shown that physical labor, unhealthy lifestyle, diabetes, hypertension, hyperglycemia, hyperlipidemia, depression, and cerebrovascular disease risk are suspected risk factors for the occurrence of MCI in the elderly, olfactory hypothyroidism, introverted personality, and the ApoE epsilon type 4 allele can be used as an early indication for the occurrence of MCI, ApoE E 4 genotype and L DL has interaction.
5. prospective studies show: demographic characteristics (age, female, lower level of Education), history of disease (diabetes and cerebral hemorrhage), ApoE - E 4 genotype carriers, high blood sugar, cholesterol and LDL and introversion, anxiety personality characteristics are the risk factors affecting the outcome, insisting on mental labor, healthy lifestyle, and reducing diabetes, Hypertension, hyperglycemia, hyperlipidemia, and the risk of cerebrovascular disease are the main means to prevent cognitive impairment of the elderly. Introverted personality and carrying ApoE - epsilon 4 allele can be used as an early indication of cognitive impairment.
6. by comparing the influencing factors of the occurrence of mild cognitive impairment in the elderly population with the influence factors of cognitive impairment, it is found that there is a high consistency, suggesting that early intervention in the community MCI population may play an important role in the prevention of cognitive impairment and even the prevention of Alzheimer's disease.

【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2009
【分類號(hào)】：R749.1;R181.3

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