臺灣博碩士論文加值系統

目前阿茲海默氏失智症的盛行率和發生率隨著人口老化而有上升的趨勢， 其病理學上的變化主要有老化斑、 神經纖維糾結、 以及後來的神經原喪失。目前阿茲海默氏失智症的治療是以乙醯膽鹼酯酶抑制劑為主，希望能藉著提高藥物使用劑量，來間接提高腦部乙醯
膽鹼酯酶之抑制，進而來提高臨床之療效， 但是並不是每一位病人
皆對此治療有良好之反應。因此我們使用毛細管電泳檢測藥物乙醯膽
鹼酯酶抑制劑: donepezil 之血中濃度， 且分析此血中濃度和病人
治療反應之相關性，我們發現高濃度的藥物對治療並沒有較好的治療
反應。治療時已是較嚴重的失智症，以 CDR-SB (Clinical Dementia
Rating-Sum of Boxes)評估，則治療效果越差。但若使用另外一項常
用的評估量表:簡易智能測驗(Mini-Mental Status Examination;
MMSE)來評估時,治療前MMSE 分數較高的病人也較難有進步空間。我
們也發現臺灣整體而言, 約有百分之五十八至六十的阿茲海默氏失
智症的病人，對此些乙醯膽鹼酯酶抑制劑有正面反應，且此反應和其
本身的年齡、教育程度、性別，及E 型脂蛋白基因多型性並無顯著相
關性。但E 型脂蛋白基因是被公認的是和阿茲海默失智症相關的基
因，因此和阿茲海默失智症相關基因的角色釐清是需要 。由於血管
加壓素可以分解乙型類澱粉，因此血管加壓素基因[Angiotensin
2converting enzyme (ACE) gene]是另一個被推論和阿茲海默失智症
相關的基因 。然而血管加壓素基因多型性對在阿茲海默失智症的影
響，會隨著種族的不同而有差異，我們收錄257 位阿茲海默失智症的
病人和137 位非失智的對照組，來檢驗血管加壓素基因和阿茲海默失
智症的相關性，並且去分析相對於不同血管加壓素基因多型性的情況
下，血管加壓素濃度的高低。我們的結果發現相對其他基因組合， I/I
同型合子相對上是顯著的保護因子(p=0.040, OR=0.584,
95%CI:0.349-0.976)，且I/I 族群中其血中血管加壓素濃度，相對
於其他基因型是比較低的(114.79±31.32 ng/mL, p=0.023)。
失智症的早期診斷和治療效果是相關的, 因此我們翻譯及檢定美
國聖路易華盛頓大學發展出來之「AD8 極早期失智症篩檢量表」中文
版在台灣的適用性。我們收集了共239 位正常與阿茲海默氏失智症的
病人來檢定此量表之適用性。在區別正常組(CDR=0) 和極早期失智症
組 (CDR=0.5)的判定值是2，且有95.89%的敏感度和78.7%的特異
性，在區別正常組（CDR=0）和失智症組（CDR≧0.5）時，其判斷值
也是2，其敏感度為97.6%，且特異性為78.07%。
此論文中的研究從乙醯膽鹼酯酶抑制劑臨床療效評估開始, 而
進一步檢驗AD8 極早期失智症篩檢量表，來篩檢極早期失智症以進一
步提高治療效果，以及檢測血管加壓素基因和阿茲海默失智症的相關
性。目前的研究尚未完全解決所有的問題, 特別是在服用乙醯膽鹼酯
酶抑制劑單一劑量，與多次服用後donepezil 血中濃度是否有差別，
病人身體中CYP450 基因型和donepezil 濃度是否相關， 以及目前
donepezil 5mg，以及未來要研究的10 mg 甚至是23mg，是否對不同
的認知功能有不同的改變及影響。

The prevalence and incidence of Alzheimer’s disease (AD) is
increasing with aging. Pathological hallmarks for AD are mainly senile plaque, neurofibrillary tangle, and neuronal loss eventually. Currently the treatment of AD is mainly focused on acetyl-cholinesterase inhibitors(AChE-I)However, not every AD patient will respond to the treatment of AChE-I. Therefore, we conducted a study to measure and analyze the plasma concentration of AChE-I: donepezil in relation to the clinically therapeutic response. We have found that higher plasma concentration of doenepzil did not provide better therapeutic response. AD patients with their higher initial sum of boxes for clinical dementia rating (CDR) were
not good respond to the treatment as well as the higher initial Mini-Mental Status Examination (MMSE) score. In general, 58-60% of our AD patients will respond to these treatments regardless of age,education, gender, and their apo-lipoprotein E genotypes (ApoE),although ApoE genotype is a putative genetic factor to AD. Beyond ApoE gene, given to Angiotensin converting enzyme (ACE) can degrade the beta-amyloid, ACE gene is a putative genetic factor to AD, but its 5 effect was varied with races. We have recruited 257 AD patients and 137 non-demented Taiwanese to examine the genetic association and the ACE plasma protein level in relation to the various ACE genotypes. Our study has shown ACE insertion homozygote was a protective factor to AD
(p=0.040, OR=0.584, 95%CI: 0.349-0.976), for its lower ACE plasma protein level (114.79±31.32 ng/mL, p=0.023) compared to other genotypes.
The early diagnosis of AD is related to the therapeutic response. In order to diagnose AD at its early stage, we have translated and validated the AD8 questionnaire developed by Washington University in St Louis. We have recruited 239 normal cognitive and AD subjects into analyses. Our results have shown that the cut-off values were both 2 in differentiating normal (CDR=0) from very mild dementia (CDR=0.5) with the sensitivity 95.9% and specificity 78.7% and in differentiating normal (CDR=0) from dementia (CDR≧0.5) with the sensitivity 97.6% and specificity 78.1%, respectively.
My study began at evaluating clinically therapeutic response of acetyl-cholinesterase inhibitors to AD, validating AD8 questionnaire to screen early AD in order to have better therpaetic response in AD patients 6 in their early stage, and examining the association of ACE gene and AD.
Current study results are not sufficient to answer the questions for the treatment of donepezil to AD, especially in the difference of plasm concnetration, if any, between single dose and multiple doses of donepezil in AD patients. We also have to clarify whether cytochrome P450 will effect the donepezil concentration, and the various cognitive
responses, if any, under current dosage of donepezil 5 mg and coming higher dosage, 10 mg or 23 mg in the future.

Chapter 1
Current status of Alzheimer’s disease ----------------------------------11
1.1. The prevalence and incidence of Alzheimer’s disease----------11
1.2. The pathogenesis of Alzheimer’s disease--------------------------15
1.3. Current treatment of Alzheimer’s disease------------------------18
1.3.1. N-methyl D-aspartate antagonist---------------------------------20
1.3.2. Acetyl-cholinesterase inhibitors-----------------------------------21
1.4. The therapeutic outcome of Acetyl-cholinesterase
Inhibitors in Alzheimer’s disease---------------------------------24
1.4.1. The questions of treatment we faced----------------------------26
1.4.1.1 Hypothesis: Can higher dosage of cholinesterase
inhibitors provide better therapeutic outcomes---------------27
1.4.1.2 Factors related to the therapeutic outcomes ----------------29


Chapter 2
Predicting therapeutic response of cholinesterase
inhibitors in Alzheimer’s disease ---------------------------------------31
2.1 Is increased acetyl-cholinesterase inhibition associated
with therapeutic response? ----------------------------------------------32
2.2 Developing the study to examine the therapeutic response
of donepezil to patient with Alzheimer’s disease--------------------33
2.2.1. Recruiting Patients -----------------------------------------------------35
2.2.2. Evaluating therapeutic responses: the psychometrics-----------37
2.2.3. The Apo-lipoprotein E genotype-------------------------------------38
2.2.4. The measurement of plasma concentration of
doenepzil through capillary electrophoresis---------------------39
2.2.4.1 The donepezil---------------------------------------------------------40
2.2.4.2 Conditions for capillary electrophoresis------------------------41
2.2.4.3 Plasma extraction----------------------------------------------------45
2.2.4.4 Sample preparation and method validation--------------------46
2.3 Results----------------------------------------------------------------------48
2.4 Discussion ------------------------------------------------------------------53

Chapter 3
Prospect to increase the therapeutic response and identifying the genetic feature of Alzheimer’s disease: early diagnosis and the role of angiotensin converting enzyme gene ------------------------62
3.1 The therapeutic response among various stage of dementia------62
3.2 Validating AD8-Chinese version questionnaire to screen very mild dementia------------------------------------------------------------64
3.2.1.1 Clinical Dementia Rating Scale-----------------------------------71
3.2.1.2 Translation and validation of AD-8 questionnaire-------------73
3.2.1.3 Participants and Psychometrics------------------------------------75
3.2.1.4 Results and the application of AD8-Chinese version-----------77
3.3 The angiotensin converting enzyme gene in
Alzheimer’s disease--------------------------------------------------------81
3.3.1 The angiotensin converting enzyme gene and
Alzheimer’s disease in African American
and Caucasian American------------------------------------------------85
3.3.2 The angiotensin converting enzyme gene and Alzheimer’s disease in Taiwanese---------------------------------------------------93
3.3.3 Conclusion and discussion ------------------------------------------100

Chapter 4
Limitations of current results and prospects to the further studies
4.1 The concentration of donepezil in individuals taking a single dose of donepezil and in cognitive response in AD patient.--------------------------------------------------------------------104
4.2 The effects of cytochrome P450 gene polymorphism to the
concentration of donepezil----------------------------------------------107

Reference----------------------------------------------------------------------109
Tables (I~XXV) ------------------------------------------------------------- 141
Figures (I~VIII)--------------------------------------------------------------156
Appendix ----------------------------------------------------------------------164
Publication List---------------------------------------------------------------179

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