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研究生:孫瑜
研究生(外文):Yu Sun
論文名稱:同胱胺酸與血管病之危險性
論文名稱(外文):Homocysteine and the Risk of Vascular Diseases
指導教授:簡國龍簡國龍引用關係
指導教授(外文):Kuo-Liong Chien
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:預防醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:122
中文關鍵詞:同胱胺酸大腦白質病變中風心血管疾病失智症
外文關鍵詞:homocysteinecerebral white matter lesionstrokecoronary heart diseasedementia
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背景:
同胱胺酸是否是血管病的獨立危險因子,我們提出一些可能的假說:同胱胺酸有可能造成血流動力學的改變而減緩流速,進而造成血管動脈硬化;可能造成腦部大腦白質病變,進而引發中風及失智症;同胱胺酸是血管病的危險因子;高血清同胱胺酸與失智症有關,如果降低血清同胱胺酸,可能可以改善智力,或阻止智力惡化。
研究方法:
針對以上的假設,我們執行以下計劃:1.觀察性研究:觀察不同濃度的同胱胺酸對頸動脈與椎動脈的血流動力影響;2.病例對照研究:有大腦白質病變者其同胱胺酸濃度是否與無病變者不同;3.長期追蹤研究:同胱胺酸的濃度是否為未來發生腦中風及心臟病的預測因子;4.隨機雙盲研究:維他命療法對降同胱胺酸及智力改善或減緩智力退化是否有臨床效用。
結果:
同胱胺酸並不影響大血管之血流動力學。同胱胺酸為大腦白質病變之危險因子,每增加1 μmol/L同胱胺酸,其發生白質病變之相對危險值為1.15 (95% CI, 1.01-1.31)。在長期世代追蹤研究,平均追蹤時間11.95年,同胱胺酸高的族群,其發生腦中風的危險並無顯著增加,但發生心血管疾病之危險性及死亡率有顯著增加。我們定出臨床上最適當的切點,發現同胱胺酸大於9.47 μmol/L者,發生心血管病之危險為小於此值的人的2.3倍 (95% CI,1.24-4.18),大於11.84 μmol/L者,死亡之危險為2.4倍(95% CI,1.76-3.32)。降同胱胺酸維他命療法之隨機雙盲實驗,治療半年後,維他命組,血清中葉酸及B12濃度明顯高於用安慰劑組,且同胱胺酸濃度在治療組也明顯低於對照組,然而此二組智能之變化並沒有因用維他命治療而有不同。
結論:
同胱胺酸並不影響血管的血流動力,但與微小血管產生的大腦白質病變有關。長期追蹤無症狀之成人,同胱胺酸並不會增加發生腦中風的危險,但卻是心血管病及死亡之危險因子。以降低同胱胺酸之維他命療法,對阿茲海默症患者之智能改善,沒有明顯的幫助。
Background
The relationship between elevated plasma homocysteine (Hcy) and vascular disease is stronger in retrospective than in prospective studies. We proposed the following 4 hypotheses: 1. Hcy may influence the hemodynamic flow of cerebral arteries and then may further induce atherosclerotic change; 2. Hcy may induce microangiopathy and lead to cerebral white matter change which may be related to future stroke and dementia; 3. Baseline Hcy may be related to future vascular event; 4. Hcy-lowering therapy with vitamin supplementation might be benefit for persons with dementia.
Material and methods
We conducted a cross-sectional study to explore the relationship between Hcy and the hemodynamic status of carotid and vertebral artery; a case-control study for Hcy and cerebral white matter lesions; a cohort study for Hcy and long-term vascular events; an experimental randomized control trial study for Hcy-lowering therapy on dementia.
Results
Hcy was not associated with the hemodynamic change on the extracranial cerebral arteries. However, Hcy is an independent risk factor for cerebral white matter change (multivariate RR 1.15, 95% CI 1.01-1.31). In the prospective cohort study with median 11.95 years of follow-up, participants with Hcy more than 9.47 µmol/L had a 2.3-fold risk for cardiovascular events (95% CI, 1.24-4.18, p=0.008), and participants with Hcy more than 11.84 µmol/L had a 2.4 fold risk for death (95% CI, 1.76-3.32, p<0.0001). Multivitamin supplements significantly elevated the concentration of vitamin B12 (p<0.0001) and folic acid (p<0.0001) and lowered the plasma homocysteine concentration (p=0.004) after 26 weeks’ treatment. However, no significant differences between the vitamin and placebo groups in the scores of cognition and activities of daily living were found.
Conclusions
Hcy was not associated with the hemodynamic change on the large extracranial cerebral arteries. The effects of Hcy on the brain may be related to cerebral microangiopathy. Homocysteine was significantly related to the cardiovascular events and all-cause death, with optimal cutpoint values as 9.47µmol/L and 11.84µmol/L respectively. Oral supplements by over-the-counter multi-vitamins containing B6, B12, and folic acid decreased Hcy concentration in patients with mild to moderate Alzheimer’s dementia. However, there were no statistically significant beneficial effects on cognition and function for daily living.
誌謝 2
中文摘要 4
Abstract 6
Chapter 1. Introduction and literature review 16
1.1 Historic aspects of homocysteine and vascular disease 16
1.2 Biochemistry, metabolism and determinants of serum homocysteine 17
1.2.1 Source of homocysteine 17
1.2.2 Methionine cycle (Figure 1) 17
1.2.3 Determinants of serum homocysteine 17
1.3 Vascular pathology and pathophysiology of hyperhomocysteinemia 18
1.3.1 Vascular pathology of hyperhomocysteinemia 18
1.3.2 Plausible mechanism of vascular damage by hyperhomocysteinemia 18
1.4 Homocysteine as a risk factor for vascular diseases 19
1.4.1 Homocysteine, hemodynamics and atherosclerosis 19
1.4.2 Homocysteine, microangiopathy and cerebral white matter lesions (WML) 19
1.4.3 The association between total serum homocysteine and clinical vascular events 20
1.5 The points favor or not favor on a causal relationship between Hcy and vascular diseases or cognitive impairment 22
1.5.1 The points in favor of a causal relationship between Hcy and vascular diseases 22
1.5.2 The points that cast doubt on a causal relationship between Hcy and vascular diseases 23
1.6 Homocysteine as a risk factor for dementia 24
Chapter 2. Hypotheses and objectives 25
2.1 Hypotheses 25
2.2 Objectives 25
Chapter 3. Subjects and Methods (Figure 2) 26
3.1 Impacts of homocysteine on hemodynamic status 26
3.1.1 Participants 26
3.1.2 Ultrasound procedure and hemodynamic measurements 26
3.1.3 Laboratory analysis 27
3.1.4 Statistical analysis 27
3.2 Homocysteine and cerebral white matter lesions (WML) on MRI 28
3.2.1 Participants 28
3.2.2 MRI protocol 29
3.2.3 Statistical analysis 29
3.3 Homocysteine and long-term vascular events (Chin-Shan cohort) 30
3.3.1 Participants and study design 30
3.3.2 Ascertainment of events 30
3.3.3 Measurements of serum homocysteine and other biochemical variables 31
3.3.4 Statistical methods 31
3.4 Homocysteine lowering clinical trial on Alzheimer’s disease 33
3.4.1 Participants and study design 33
3.4.2 Study regimens 34
3.4.3 Assessment and outcome measures 35
3.4.4 Outcome measures 35
3.4.5 Safety evaluations 36
3.4.6 Data analysis 37
Chapter 4. Results 39
4.1 Homocysteine and the hemodynamic status of the extracranial large arteries (Table I-1 to Table I-7) 39
4.2 Homocysteine and microangiopathy related cerebral WML (Table II-1 to Table II-2) 40
4.3 Homocysteine and long-term clinical vascular events (Chin-Shan cohort) (Table III-1 to Table III-4) 40
4.4 Homocysteine lowering clinical trials on dementia (Table IV-1 to Table IV-4) 42
4.4.1 Efficacy of homocysteine –lowering vitamin therapy 42
4.4.2 End points 43
4.4.3 Safety 44
Chapter 5. Discussion 46
5.1 Homocysteine and cerebral hemodynamic status 46
5.2 Homocysteine and cerebral white matter lesions (WML) 50
5.3 Homocysteine and clinical vascular events 52
5.4 Homocysteine-lowering vitamin therapy on dementia 55
Chapter 6. Summary, Conclusions and Future direction 59
6.1 Summary of the findings in these serial studies 59
6.2 Strength and limitations 61
6.3 Clinical implications 65
6.4 Conclusions 66
6.5 Future research directions 68
References 70

Figures
Figure 1. Metabolic pathway of homocysteine 92
Figure 2. Study design of four serial studies 93
Figures for homocysteine and cerebral hemodynamic status 94
Figure I-1. Duplex image (including B-mode and Doppler) of the common carotid artery 94
Figure I-2. Duplex image (including B-mode and Doppler) of the vertebral artery 95
Figures for homocysteine and cerebral white matter lesions 96
Figure II-1. T2-weighted brain MR image with hyperintensity signals (pointed by white arrow) on the periventrcular (left) and subcortical area (right) 96
Figures for homocysteine and long-term vascular events 97
Figure Ⅲ-1. Relative risk for stroke during a median follow-up of 11.95 years, according to quartile of homocysteine concentration at baseline (1994-1995) in the Chin-Shan Community Cardiovascular Study 97
Figure Ⅲ-2. Relative risk for CHD during a median follow-up of 11.95 years, according to quartile of homocysteine concentration at baseline (1994-1995) in the Chin-Shan Community Cardiovascular Study 98
Figure Ⅲ-3. Relative risk for all-cause death during a median follow-up of 11.95 years, according to quartile of homocysteine concentration at baseline (1994-1995) in the Chin-Shan Community Cardiovascular Study 99
Figure Ⅲ-4. Receiver-Operating Characteristic Curves for coronary heart disease (CHD) events during a median follow-up of 11.95 years 100
Figure Ⅲ-5. Receiver-Operating Characteristic Curves for death events during a median follow-up of 11.95 years 101
Figures for homocysteine-lowering therapy 102
Figure Ⅳ-1. Patients enrollment and completion throughout the study period 102
Figure Ⅳ-2. Odds ratios for the effects on cognition and daily living scores of 26 weeks of combined multivitamins or placebo in patients with mild or moderate Alzheimer’s dementia 103
Figure Ⅳ-3. Mean changes form baseline in cognition scale in the homocysteine-increase and homocysteine-decrease groups with 26 weeks of combined multivitamins or placebo in patients with mild or moderate Alzheimer’s dementia 104

Tables

Tables for homocysteine and cerebral hemodynamic status 105
Table Ⅰ-1. Characteristics of the study population according to homocysteine quartiles 105
Table Ⅰ-2. Hemodynamic parameter values of the carotid artery according to homocysteine quartiles 106
Table Ⅰ-3. Hemodynamic parameter values of the vertebral artery according to homocysteine quartiles 107
Table Ⅰ-4. Adjusted mean values of flow parameters of carotid artery across homocysteine quartiles 108
Table Ⅰ-5. Adjusted mean values of flow parameters of vertebral artery across homocysteine quartiles 109
Table Ⅰ-6. Relations of plasma homocysteine to the flow parameter of carotid artery 110
Table Ⅰ-7. Relations of plasma homocysteine to the flow parameter of vertebral artery 111
Tables for homocysteine and cerebral white matter lesions 112
Table Ⅱ-1. Demographic, laboratory data and homocysteine levels in subjects with normal brain MRI and patient with white matter lesions (WML) on MRI 112
Table Ⅱ-2. Effects of homocysteine on the risk of white matter lesions on the brain MRI adjusting for potential confounders 113
Tables for homocysteine and long-term vascular events 114
Table Ⅲ-1 .Characteristics of the study population according to homocysteine quartiles 114
Table Ⅲ-2. Incidence cases, person-years, incidence rates, and relative risk (RR) for stroke, CHD and all-cause death outcomes during a median follow-up of 11.95 years, according to quartile of homocysteine concentration at baseline (1994-1995) in the Chin-Shan Community Cardiovascular Study. 115
TableⅢ-3. Subgroup analyses of relative risk (RR) for ischemic stroke, hemorrhagic stroke, and ischemic versus hemorrhagic stroke; RR for cardiovascular (CV) death, non-cardiovascular (non-CV) death, and cardiac versus non-cardiac death in fully adjusted model 116
Table Ⅲ-4. Sensitivity, specificity and best Youden''s index of the cutoff values, and the hazard ratio for the risk of stroke, cardiovascular events and all-cause of death under the cutoff value of homocysteine 117
Tables for homocysteine lowering therapy 118
Table Ⅳ-1. Demographic, baseline Hcy, B12, folic acid and cognitive function of the study population. 118
Table Ⅳ-2. Serum concentrations from baseline to 26 weeks with combined multivitamins or placebo in patients with mild to moderate Alzheimer''s dementia. Values are median interquartile range. 119
Table Ⅳ-3. Changes from baseline to 26 weeks in cognition and daily living function with combined multivitamins or placebo in patients with mild to moderate Alzheimer''s dementia (intent-to-treat population). 120
Appendix 122
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