臺灣博碩士論文加值系統

隨著台灣人口逐漸老化，失智症人口亦逐年增加。失智症所耗費之社會成本是不容小覷的，因此如何預防失智症的發生，是一個重要的健康議題。H2受體阻抗劑為治療胃潰瘍的第一線用藥，但國人服用藥品喜愛搭配胃藥的習性，使得H2受體阻抗劑濫用的狀況日益增加。近來有研究顯示，長期服用H2受體阻抗劑可能會促使維生素B12造成缺乏，而維生素B12缺乏會導致罹患失智症的風險提高。
本研究旨在探討服用H2受體阻抗劑與失智症的相關性。本研究為14年的回溯性世代研究，使用具有台灣人口代表性的台灣健保資料庫2000年百萬歸人檔為材料，納入65歲以上的老年族群，分暴露組為有服用H2受體阻抗劑與非暴露組為沒有服用H2受體阻抗劑的兩組，再依性別、年齡做1:1的配對，將兩組持追蹤至失智症發生，死亡(退保)，或至2013年12月31日。以存活分析曲線(Kaplan-Meier survival curve)了解服用與未服用H2受體抗阻斷劑與罹患失智症的差異，進一步以Cox迴歸分析計算罹患失智症的相對危害比(Hazard ratio, HR)及95%信賴區間(95% Confidence Interval, 95% CI)。
研究結果發現在服用H2受體阻抗劑的65歲以上老人罹患失智症的風險明顯大於未服用H2受體阻抗劑的老年族群 (Adjusted HR= 2.46, 95% CI 1.99-3.05 )。而在劑量效應方面，低暴露組1-180 DDD (Adjusted HR =2.42 95% CI, 1.88-3.10)，中暴露組180-540 DDD (Adjusted HR =2.58, 95% CI, 2.04-3.26) ，高暴露組大於540 DDD (Adjusted HR=2.35, 95% CI, 1.81-3.04)，並沒有顯著的劑量效應，有服用H2受體阻抗劑的老年族群，皆有風險存在。
本研究結果顯示服用H2受體阻抗劑與罹患失智症的風險有顯著相關。因此，建議醫療人員避免過度開立H2受體阻抗劑。

As life expectancy of people in Taiwan grows, the number of people with dementia increases year by year. The social cost of dementia can not be underestimated. Therefore, it is an important health issue to prevent the occurrence of dementia.
H2 blocker is the first-line medication for treating gastric ulcers. However, the habits of using medicines in combination with stomach medicines in Taiwan have led to an increasing abuse of H2 blocker. Recent studies have shown that long-term use of H2 blocker may contribute to vitamin B12 deficiency, and vitamin B12 deficiency may increase the risk of dementia.
The purpose of this study was to investigate the association between H2 blocker and dementia in elderly patients. This was a retrospective population-based cohort study for 14 years and using the Taiwan Health Insurance Database 2000 (LHID2000). This study included elderly populations over 65 years old. The study population was divided into exposure group of H2 blocker and non-exposed group who did not use H2 blocker. These two groups were 1:1 matched by age, sex and comorbidities and were all followed until the occurrence of dementia, death, withdrawal from National Health Insurance program or until December 31, 2013, which occurred first. The Kaplan-Meier survival curve was used to understand the difference between the dementia in patients using and not using H2 blocker. The Cox regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CI) for the risk of incident dementia.
The study found that the risk of dementia in the elderly over the age of 65 who used the H2 blocker was significantly greater than that of the elderly group who did not use the H2 blocker (Adjusted HR = 2.46, 95% CI 1.99-3.05). In terms of dose effects, the low exposure group was 1-180 DDD (Adjusted HR = 2.42 95% CI, 1.88-3.10), and the exposure group was 180-540 DDD (Adjusted HR = 2.58, 95% CI, 2.04-3.26). The exposure group was greater than 540 DDD (Adjusted HR = 2.35, 95% CI, 1.81-3.04), and there was no significant dose-dependent. There was risk in the elderly population who took the H2 blocker.
The results of this study showed that the use of H2 blocker is significantly associated with the risk of dementia in elderly patients. Therefore, it is recommended that patients avoid over using H2 blocker.

目錄 I
表目錄 III
圖目錄 IV
附錄目錄 V
中文摘要 VI
英文摘要 Ⅶ
第一章 緒論 1
第一節 研究背景及重要性 1
第二節 研究動機 4
第三節 研究目的 7
第二章 文獻探討 8
第一節 失智症的診斷 8
第二節 評估失智症的工具 9
第三節 失智症的種類 11
第四節 失智症相關危險因子 13
第五節 失智症的治療藥物 18
第六節 H2受體阻抗劑作用機轉與藥品種類 19
第七節 H2受體阻抗劑與罹患失智症之探討 21
第三章 材料與方法 23
第一節 研究材料及工具 23
第二節 研究架構 26
第三節 研究對象 28
第四節 統計分析 30
第五節 研究倫理 30
第四章 結果 32
第一節 研究族群選取與分組流程 32
第二節 研究族群基本特性分布 33
第三節 H2受體阻抗劑與失智症風險分析 36
第五章 討論 49
第六章 結論與建議 58
參考文獻 59

Alzheimer's Association. (2018). 2018 Alzheimer's disease facts and figures. Alzheimer's & Dementia, 14(3), 367-429.
Alzheimer disease international (2015). Types of dementia.
Anstey, K.J., von Sanden, C., Salim, A., and O'kearney, R. (2007). Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol 166(4), 367-378.
Anthony, J.C., Breitner, J.C., Zandi, P.P., Meyer, M.R., Jurasova, I., Norton, M.C., and Stone, S.V.(2000). Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study. Neurology 54(11), 2066-2071.
Avadhani, R., Fowler, K., Barbato, C., Thomas, S., Wong, W., Paul, C.,Aksakal, M., Hauser, T.H., Weinger, K., and Goldfine, A.B. (2015). Glycemia and cognitive function in metabolic syndrome and coronary heart disease. Am J med 128(1), 46-55.
Boustani, M., Hall, K.S., Lane, K.A., Aljadhey, H., Gao, S., Unverzagt, F., Murray, M.D., Ogunniyi, A., and Hendrie, H. (2007). The association between cognition and histamine‐2 receptor antagonists in african americans. J Am Geriatrics So 55(8), 1248-1253.
Breitner, J.C., Welsh, K.A., Helms, M.J., Gaskell, P.C., Gau, B.A., Roses, A.D., Pericak-Vance, M.A., and Saunders, A.M. (1995). Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging 16(4), 523-530.
Carlson, M.C., Tschanz, J.T., Norton, M.C., Welsh-Bohmer, K., Martin, B.K., and Breitner, J.C.(2002). H2 histamine receptor blockade in the treatment of Alzheimer disease: a randomized, double-blind, placebo-controlled trial of nizatidine. Alzheimer Dis Assoc Disord 16(1), 24-30.
Corrada, M.M., Brookmeyer, R., Paganini‐Hill, A., Berlau, D., and Kawas, C.H. (2010). Dementia incidence continues to increase with age in the oldest old: the 90+ study. Ann Neurol 67(1), 114-121.
Crane, P.K., Walker, R., Hubbard, R.A., Li, G., Nathan, D.M., Zheng, H., Haneuse, S., Craft, S., Montine, T.J., and Kahn, S.E. (2013). Glucose levels and risk of dementia. N Engl J Med 369(6), 540-548.
Da Matta, S.M., Janaina Matos, M., Kummer, A.M., Barbosa, I.G., Teixeira, A.L., and Silva, A.C. (2014). Cognitive alterations in chronic kidney disease: an update. J Bras Nefrol 36(2), 241-245.
Deckers, K., Camerino, I., van Boxtel, M.P., Verhey, F.R., Irving, K., Brayne, C., Kivipelto, M., Starr, J.M., Yaffe, K., and de Leeuw, P.W. (2017). Dementia risk in renal dysfunction : A systematic review and meta-analysis of prospective studies. Neurology 88(2), 198-208.
Desmond, D.W., Moroney, J.T., Sano, M., and Stern, Y. (2002). Incidence of dementia after ischemic stroke: results of a longitudinal study. Stroke 33(9), 2254-2260.
Gomm, W., von Holt, K., Thome, F., Broich, K., Maier, W., Fink, A.,Doblhammer, G., and Haenisch, B. (2016). Association of proton pump inhibitors with risk of dementia: A pharmacoepidemiological claims data analysis. JAMA Neurol 73(4), 410-416.
Gottesman, R.F., Albert, M.S., Alonso, A., Coker, L.H., Coresh, J., Davis, S.M., Deal, J.A., McKhann, G.M., Mosley, T.H., and Sharrett, A.R. (2017). Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk In Communities (ARIC) cohort. JAMA neurology, 74(10), 1246-1254..
Gray, S.L., Anderson, M.L., Dublin, S., Hanlon, J.T., Hubbard, R., Walker, R., Yu, O., Crane, P.K.,and Larson, E.B. (2015). Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 175(3), 401-407.
Gray, S.L., Walker, R., Dublin, S., Haneuse, S., Crane, P.K., Breitner, J., Bowen, J., McCormick, W., and Larson, E.B. (2011). Histamine‐2 receptor antagonist use and incident dementia in an older cohort. J Am Geriatrics Soc 59(2), 251-257.
Hanlon, J.T., Landerman, L.R., Artz, M.B., Gray, S.L., Fillenbaum, G.G., and Schmader, K.E. (2004). Histamine2 receptor antagonist use and decline in cognitive function among community dwelling elderly. Pharmacoepidemiol Drug Saf 13(11), 781-787.
Howland, R.D., Mycek, M.J., Harvey, R.A., and Champe, P.C. (2006). Pharmacology:(Lippincott Williams & Wilkins).
Lam, J.R., Schneider, J.L., Zhao, W., and Corley, D.A. (2013). Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 310(22), 2435-2442.
Launer, L., Jama, J.W., Ott, A., Breteler, M., Hoes, A., and Hofman, A. (1997). Histamine H2 blocking drugs and the risk for Alzheimer’s disease: the Rotterdam Study. Neurobiol Aging 18(2), 257-259.
Livingston, G., Sommerlad, A., Orgeta, V., Costafreda, S.G., Huntley, J., Ames, D., Ballard, C., Banerjee, S., Burns, A., Cohen-Mansfield, J. ... & Cooper, C. (2017). Dementia prevention, intervention, and care. Lancet 390(10113), 2673-2734.
Perneczky, R., Wagenpfeil, S., Lunetta, K.L., Cupples, L.A., Green, R.C., DeCarli, C., Farrer, L.A., and Kurz, A. (2009). Education attenuates the effect of medial temporal lobe atrophy on cognitive function in Alzheimer's disease: the MIRAGE study. J Alzheimers Dis 17(4), 855-862.
Rocca, W.A., Mielke, M.M., Vemuri, P., and Miller, V.M. (2014). Sex and gender differences in the causes of dementia: a narrative review. Maturitas 79(2), 196-201.
Sanderson, M., Wang, J., Davis, D.R., Lane, M.J., Cornman, C.B., and Fadden, M.K. (2002). Co-morbidity associated with dementia. Am J Alzheimers Dis Other Demen 17(2), 73-78.
Sieben, A., Van Langenhove, T., Engelborghs, S., Martin, J.-J., Boon, P., Cras, P., De Deyn, P.-P., Santens, P., Van Broeckhoven, C., and Cruts, M. (2012). The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathologica 124(3), 353-372.
Tannenbaum, C., Paquette, A., Hilmer, S., Holroyd-Leduc, J., and Carnahan, R. (2012). A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs Aging 29(8), 639-658.
The American Geriatrics Society Beers Criteria Update Expert, P. (2015). American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc 63(11), 2227-2246.
Tzeng,N.-S.,Chung,C.-H.,Lin,F.-H.,Huang,C.-F.,Yeh,C.-B.,Huang,S.-Y.,Lu R.-B., Chang,H.-A.,Kao,Y.-C.,and Yeh,H.-W. (2018). Magnesium oxide use and reduced risk of dementia: a retrospective, nationwide cohort study in Taiwan. Cur Med Res Opin 34(1), 163-169
Whitmer, R.A., Sidney, S., Selby, J., Johnston, S.C., and Yaffe, K. (2005). Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 64(2), 277-281.
World Health Organization (2017). Dementia.
Yaffe, K., and Boustani, M. (2014). Benzodiazepines and risk of Alzheimer’s disease BMJ: British Medical Journal (Online), 349.
Chen, C.-H. (2015). 慢性阻塞性肺疾病病患在失智症增加的風險及相關因素:以台灣全人口基礎的前瞻式世代研究.中央大學資訊工程學系碩士在職專班學位論文, 1-47.
台灣失智症協會 (2018). 台灣失智症人口推估.
杜恩年, 簡意玲, 葉寶專, 胡海國, 邱銘章, 黃偉烈 (2017). 酒精相關的認知功能損害.台灣醫學 21(1), 103-112.
梁家欣, 程蘊菁, 陳人豪 (2014).失智症之重點回顧. 內科學誌 25(3), 151-157.
陳彥宇 (2012). 高血壓與失智症. 血管醫學防治季刊 (9), 18-19.
劉景寬, 戴志達, 林瑞泰, 賴秋蓮 (2000). 台灣失智症的流行病學. 應用心理研究(7), 157-169.
歐陽文貞 (2009). 老年失智症不切適藥品回顧. 台灣老年醫學暨老年學雜誌. 4(2),77-90
蔡孟軒 (2016). 台灣老年族群使用質子幫浦阻斷劑與失智症風險之相關性探討. 高雄醫學大學藥學系臨床藥學碩士班學位論文, 1-164.
蕭兆廷 (2014). 新發失智症與共病之關係. 中國醫藥大學公共衛生學系碩士班學位論文, 1-73.