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系統識別號 U0026-2204201510051600
論文名稱(中文) 頭部外傷增加失智症的相關研究
論文名稱(英文) The study of Traumatic brain injury and dementia
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 王浩洸
研究生(英文) Hao-kuang Wang
學號 S98011164
學位類別 博士
語文別 英文
論文頁數 87頁
口試委員 召集委員-陳翰容
口試委員-邱仲慶
口試委員-郭余民
口試委員-江伯敏
指導教授-蔡坤哲
中文關鍵字 頭部外傷  額顳葉癡呆  流行病學調查  神經退行性疾病 
英文關鍵字 Traumatic brain injury  Frontotemporal dementia  epidemiology  neurodegeneration 
學科別分類
中文摘要 頭部外傷是年輕人意外死亡和傷殘最主要的因素。根據台灣健保資料庫的研究,台灣每年有超過五千人因為頭部外傷而接受治療。大多數頭部外傷後會產生不同程度的症狀如暈眩、噁心、嘔吐、頭痛、神經症狀、昏迷、甚至於死亡。台灣是已開發國家,但人民的交通工具仍以機車為主。因此對於頭部外傷的重要,不可忽視。近年來頭部外傷已被視為一種連續性的疾病,會引發一連串的免疫反應及星狀細胞活化,而非單一疾病。這過程會影響日後的恢復及造成日後的神經退化疾病。創傷性腦損傷(TBI)及老年癡呆症的風險之間的關係仍存在爭議。此研究的目的是評估和創傷性腦損傷後失智在創傷性腦損傷和非創傷性腦損傷的個體的風險比較。本研究是一項回顧性隊列研究。數據來自台灣的全民健康保險研究數據庫(NHIRD)獲得。該病的診斷定義至少兩個求診的記錄或一次住院記錄。案件被歸類為每個病患依據第九次修訂臨床修改(ICD-9-CM)的國際分類分配的診斷代碼。數據用Cox比例風險回歸分析。此外,我們使用創傷性腦損傷的大鼠模型表明,TDP-43的蛋白水解增加並產生額顳葉失智狀損傷,並且在Morris水迷宮受損表演。我們研究的主要發現是腦外傷後患有老年癡呆症是一般人的1.68倍。風險調整是按照社會人口學特徵和選擇的合併症後獨立相關來矯正。創傷組的病人發生 的失智症中是更可能發生額顳葉失智(FTD)。這項研究的結果提示頭部外傷病人之間患有老年癡呆症的風險增加,特別是在額顳葉失智。大鼠出現類似於在患者發生額顳葉失智後行為。此外,行為障礙分別有可能與TDP-43的短的片段錯誤定位和積累有關。最近,慢性炎症反應,這是一個持續的,也許終身的過程被認為是可能是頭部外傷引起癡呆的機制。幾項研究已經表明,腦外傷與炎症免疫改變,包括細胞因子的水平的增加和增加的小膠質細胞活化相關聯。台灣的全民健康保險研究數據庫或許是一個合適的工具來研究頭部外傷病人和老年癡呆症。儘管有證據表明,頭部外傷病人是老年癡呆症的危險因素,進一步研究在這方面要回答這些問題,並研究是否頭部外傷病人的適當管理是有效降低老年癡呆症的發病率。
英文摘要 The relationship between traumatic brain injury (TBI) and the risk of dementia remains controversial. This study was designed to estimate and compare the risk of dementia in TBI and non-TBI individuals after TBI. This study was a retrospective cohort study. Data were obtained from the Taiwan’s National Health Insurance Research Database (NHIRD). Disease was defined on the basis of at least two NHI ambulatory claim records or one inpatient record. Cases were categorised as per the diagnosis codes assigned by the International Classification of Diseases, 9th Revision Clinical Modification (ICD-9-CM). Data were analysed by Cox proportional hazard regression. The main finding of our study were that TBI was independently associated with a 1.68 times greater risk of dementia after adjusting for sociodemographic characteristics and selected comorbidities. Frontotemporal dementia (FTD) was more likely to occur in the TBI group. Furthermore, we used a rat model of TBI to show that increased TDP-43 proteolysis following TBI produces FTD-like impairments, including abnormal limb-clasping, and impaired performances in the Morris water maze. The findings of this study suggest an increased risk of dementia among individuals with TBI, especially in FTD. NHIRD is a suitable tool to study TBI and dementia. Rats developed behavioral impairment similar to those in patients with FTD after TBI. Further, the behavioral impairments were likely associated with TDP-43 short fragment mislocalization and accumulation. Recently, a chronic inflammatory response, which is an ongoing, perhaps lifelong, process was considered as a mechanism possibly linking TBI to dementia. Several studies have demonstrated that TBI is associated with inflammatory immune alterations, including increased levels of cytokines and increased microglial activation. Although the evidence suggests that TBI is a risk factor for dementia, further research in this area is necessary to answer these questions and examine whether proper management of TBI is effective in reducing the incidence of dementia.
論文目次 Chinese abstract I
English abstract III
Acknowledgment V
Abbreviations VI
Contents VII

Chapter 1 Introduction
1.1 Traumatic brain injury. 1
1.2 The association between neurodegenerative diseases and TBI. 1
1.3 Amyloid‑β pathology is not only way to explain why TBI induces dementia. 3
1.4 Frontotemporal dementia more frequency than other dementia in TBI 3
1.5 TDP-43 inclusion body is a neuropathology hallmark of FTD 3
1.6 TDP-43 proteolysis were found in TBI 4
1.7 Thesis aim 5
Chapter 2 Population-based study on patients with TBI suggests increased risk of dementia
2.1 Backgrounds and Aims 7
2.2 Methods 9
2.3 Results 14
2.4 Discussion 17
2.5 Tables 24
Chapter 3 Traumatic brain injury causes frontotemporal dementia
3.1 Backgrounds and Aims 28
3.2 Methods 31
3.3 Results 37
3.4 Discussion 40
3.5 Tables 45
3.6 Figures 48
Chapter 4 General Discussion
4.1 Main result 53
4.2 TBI is associated with dementia 54
4.3 The mechanism to explain why a TBI may influence the incidence of dementia 54
4.4 Higher comorbidities were found in TBI 56
4.5 The risk between early-onset and late-onset dementias maybe different 57
4.6 FTD is one of common post-TBI dementia 58
4.7 Study limitations 59
Chapter 5 Conclusion 61
References 63
Appendix
Thesis-related publication 76
Other publication during graduate program 84
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