项目来源

台湾省政府科研基金(GRB)

项目主持人

冯汉中

项目受资助机构

台湾省长庚医疗神经内科

财政年度

2013,2012

立项时间

未公开

项目编号

NSC101-2314-B182A-070-MY2

项目级别

省级

研究期限

未知 / 未知

受资助金额

3200.00千元台币

学科

临床医学；生物技术(医)

学科代码

未公开

基金类别

商品化/学术补助

关键词

阿兹海默氏症 ; 失智症 ; 基因 ; 多型性 ; 基因复制数变异 ;

参与者

徐文俊；陈琼美

参与机构

未公开

项目标书摘要：I.背景：阿滋海默症是一种神经退化性疾病，其不单有渐进式认知功能退化，更会出现各种精神行为症状。约50%至80%的失智症病患会有精神行为症状，其中包括精神症状(如幻觉),忧郁，躁动，攻击行为等。这些症状往往较认知功能的缺失造成照顾者更重的负担。目前己有多个研究显示失智症的精神行为的发生与遗传因子有相关性。其中包括戊型脂蛋白(apolipoprotein E),细胞白介素乙型第一因子促进子(interleukin 1-beta promoter),血清素转运蛋白(serotonin transporter)基因的多型性。另外人们发现在人类基因体中的基因复制数变异对於疾病有着深远的影响，更进一步帮助科学家们解释各种基因变化和疾病间的关系。对於失智症的研究，基因复制数变异已被发现与失智症的发生及其发病年龄有关。而且，亦有证据显示这些基因复制数变异在失智症的临床表徵的致病机转亦扮演重要的角色。基因复制数变异可以包含整个基因或是基因中可被转录的部分或甚至是一些只具有调节功能的部分；因此，这些变异造成疾病的原因则可能更为多元。至目前为止，虽然我们己累积了不少的研究资料，发现有多种精神疾病和不同层次的遗传因素有关。但是，基因复制数变异对失智症的精神行为症状的影响却尚未被深入探讨。基因复制数变异是个人拥有的基因图谱间重要的微少差异，而这是研究失智症的各种表徴型及基因型相关性的优质工具。II.实验目的：本计划目的是寻找影响失智症病患精神行为症状的遗传因素。我们将透过分析在各受试者的精神行为症状的种类及对治疗反应与其带有的人类基因复制数变异的多型性分布比例，来估算出这些基因复制数变异及其间之相互作用是否和精神行为症状有关，并试推断这些这些基因复制数变异影响力之强度。III.实验设计：本研究为二年期的前瞻性临床观察实验。IV.研究方法：样本收集我们将采纳失智症病患四百五十名及认知功能健全者五十名作为样本进入本研究。我们将为经同意成为研究对象的受试者进行背景资料的收集，包括性别、年龄、教育程度、身体质量指数、抽烟状态、中风病史、血压、三酸甘油脂血中浓度、胆固醇血中浓度、血醣浓度、药物使用状态。我们将利用神经心智评估工具(CASI,MMSE及CDR)及精神行为症状量表(NPI及BEHAVE-AD)来为受试者进行认知功能测试及精神行为症状与严重度。每位受试将被观察二年，於每六个月的追踪评估中，我们将以其精神行为的型态及严重度作为此研究的依变项(dependent variable)来分析基因复制数变异与此临床表徵之相关性。基因多型性分析在基因多型性的分析部分，我们将会利用基因复制数变异的晶片对受试的检体者进行测试，经检定的基因复制数变异将会用於测定各受试者的临床和变异数分布之相关性。我们会对研究样本进行对偶基因型(Allelelic)和单套型(Haplotypic)分析，并利用其分布比例差异来计算是否与受试者的精神行为症状呈相关性。於达到显着差异的变异数标签中选择最优者，於研究族群再进行第二阶段基因多型性相关性分析。V.预期成果及其重要性透过这个基因复制数变异对台湾族群阿症精神行为症状的研究，我们团队预期能找出各个与精神行为症状相关的基因复制数变异多型性对阿症之影响，并可估计基因与基因间，甚至基因与环境因素的交互作用对阿症所产生的冲击。此研究的重要性不仅是对基础研究提供更多的导向性研究题材，更为临床阿症的及早诊断及预後提供可能的生物标记(biomarkers)。这些可预期的发现极有可能为未来阿症的治疗及预防建立一个研发的平台。

Application Abstract: I.Background Alzheimer's disease(AD)is a neurodegenerative disorder characterized by not only progressive cognitive decline,but also a variety of behavioral and psychological symptoms in dementia(BPSD).Approximately 50%to 80%of patients diagnosed with AD present behavioural or psychiatric disturbances such as psychosis and depression.These symptoms usually may be more burdensome to caregivers then the deteriorating cognitive functions.They also lead to earlier institutionalization and increased social and economic costs.Several studies have investigated to recognized genetic risk factors for the BPSD of late-onset AD,namely the apolipoprotein E,interleukin 1-beta promoter,serotonin transporter genes polymorphisms were associated with BPSD.The discovery of Copy number variations(CNV)has had far-reaching implications for disease research,enabling scientists to correlate genetic alterations with disease.For dementia,altered CNV has been found to be related to the occurrence of the disease.Furthermore,evolving data showed that CNV may also play an important role in the characterization of the clinical presentation of dementia,such as age of onset.Copy number variants may contain entire genes or exons of individual genes and may alter non-gene regulatory regions,adding to the many possible mechanisms of disease pathogenesis.Though we have accumulating data showing that a number of psychiatric disorders are associated with different level of genetic variations,CNV has not yet been well explored for describing the mechanisms of BPSD occurrence in AD and its treatment response.CNV,as inter-individual significant minor variants,should be good candidates for the association study between phenotypes and genotypes in AD.II.Purpose In this study,we are going to evaluate the relationship between CNV and the clinical presentation of AD,namely BPSD and treatment response;in order to explore the new mechanisms of the genomic structural variations exert on the behavioral and psychological presentation and its treatment in AD.III.Study Design This project will be a two-year prospective observational study in a naturalistic out-patient clinical setting.In total,500 participants(450 AD patients and 50 cognitive healthy individuals)will be recruited.The demographical data of each participant will be recorded as the covariates in the final analysis.And each participant will be followed up for two years with comprehensive neuropsychological assessments(including CASI,MMSE,CDR,Neuropsychological inventory and BEHAVE-AD)for baseline and follow-up evaluation every 6 month interval.They will be assigned into different groups at the beginning of the study according to their baseline cognitive function.The presentation of their BPSD will be used as the dependent variables in our multivariate logistic regression model analysis.We are going to use the CNV microarray platform to assess the distribution of CNV in different assigned groups of participants.The allelele,genotype and haplotype frequencies of the CNV will be calculated and ranked.The top-ranked CNV will be further evaluated to clarify the association between those variations and the clinical presentation of our cohort.ANOVA and chi-square test will be used for testing the association mentioned above.Meanwhile,multivariate logistic regression model will be performed for analyzing the strength of association between those genetic factors and the disease progression after adjustment of the covariates.IV.Predicted outcomes and their significances With the completion of this project,we will uncover the association between CNV in human genome and the BPSD pattern in AD patients.We will also understand the impact of BPSD related CNV on AD and its magnitude on the clinical presentation of Taiwanese dementia.Furthermore,our results will shed light upon the development of biomarkers for early diagnosis and prognostic prediction in AD.

项目受资助省

台湾省