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研究生:林宜慧
研究生(外文):Yi-Huei Lin
論文名稱:探討COMT基因多態性在健康成人生命週期中對 大腦功能及結構之非線性效應
論文名稱(外文):The Inverted /U-Shaped Effect of COMT SNP on Cortical Morphology and Function in Adult Lifespan
指導教授:林慶波林慶波引用關係
指導教授(外文):Ching-Po Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:腦科學研究所
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:2016
畢業學年度:104
語文別:中文
論文頁數:71
中文關鍵詞:COMT多巴胺正常老化靜息態功能性磁振造影基於體素之形態學分析
外文關鍵詞:COMTdopaminenormal agingresting-state fMRIglobal brain analysisvoxel based morphometry
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COMT基因在人類大腦的主要作用是合成降解神經傳導物質-多巴胺所需要的酵素,其活性可直接影響多巴胺的含量。然而,基因的單核甘酸多態性變異會造成個體間的COMT酵素活性差異,進而影響其調節多巴胺的能力。過去研究針對多巴胺對行為及症狀表現的效應提出了倒U型模型假設,濃度過高或過低皆對大腦結構或功能造成不好的影響並且破壞大腦運作之協調性,嚴重甚至導致疾病的產生,像是精神分裂症、帕金森氏症和亨丁頓舞蹈症等等。但是大腦多巴胺含量並不是維持不變,可能受到老化的作用而產生變化。因此,我們希望了解健康成人之COMT基因多態性與年齡的交互作用在大腦功能及結構於老化中所扮演的角色。本研究共收集兩百九十七位健康的成年受試者,其年齡範圍界於十九歲至九十歲之間,利用年齡和COMT基因型分組以觀察基因型調控之多巴胺倒U型效應。經MRI掃描取得靜息態功能性影像及T1影像,使用資料推論方式分析全局網路連結的變化並利用以體素為基礎的型態計量學檢測大腦灰質體積的差異,以及與臨床認知分數進行相關性分析。結果顯示,在大腦功能分析中發現雙側視丘的功能性連結變化受到COMT基因和年齡的作用呈現倒U型曲線並且雙側視丘與右腦額葉中迴區及前額葉腦迴區的功能性連節變化也是受到倒U型曲線所調控。另外,於大腦結構分析中,右腦視丘和右腦顳葉中端區的灰質體積改變受到COMT基因和年齡的作用則是呈現U型曲線,此結果顯示大腦可能藉由調控局部灰質體積補償視丘功能方面之缺陷。最後,此實驗提供我們更多有關於COMT對多巴胺的作用反映在健康成人生命週期中對大腦結構及功能之非線性效應調控之間接證據。
The catechol-O-methyltransferase (COMT) gene, a dopamine (DA) enzyme, with a functional polymorphism (Val158Met) that results in a fourfold decrease in enzymatic activity and increases synaptic DA availability in Met-allele carriers. DA level influences cortical neuronal development and apoptosis, which associated with the modulation of brain structure and function, moreover, might further affect individuals’ behavioral performance. Previous findings have been reported that such DA-mediated alteration in brain follows an inverted U-shaped curve, in which the lowest and highest DA availability both result in poor outcome via modulation of brain structure and function. Therefore, we hypothesized that the COMT would interact with age to affect brain structure in terms of inverted U-shaped effects. Total of 297 normal Chinese subjects were recruited and genotyped of COMT by DNA extraction. To assess an inverted U-shaped relation in healthy aging, we divided all subjects into 6 groups in terms of COMT genotypes and age. In this study, we conducted voxel-based morphometry (VBM) and a recently developed data-driven global brain connectivity (GBC) analysis, to investigate the genetic effect of the COMT on human cortical morphology and function throughout the whole brain. Furthermore, brain regions that showed a significant COMT x age interaction effects on GBC were extracted and defined as seed regions for the following resting-state functional connectivity (rsFC) analysis. These findings suggest that COMT Val158Met modulates both gray matter morphology and functional connectivity, and a U-shaped dopaminergic model of the volume of right thalamus may imply a compensatory mechanism in response to functional deficit. This study provides extending observations of nonlinear pattern of COMT effect on dopamine level to the alteration of brain structure and function over human lifespan.
致謝.....i
中文摘要..ii
英文摘要..iv
圖目次...viii
表目次...ix
第一章 緒論
1.1 研究動機.....1
1.2 研究主題.....4
第二章 理論基礎與文獻討論
2.1 大腦老化.....6
2.2 多巴胺
2.2.1 多巴胺神經傳導路徑...10
2.2.2 多巴胺代謝基因: COMT Val158Met之基因多態性...14
2.3 COMT Val158Met的功能性討論....16
2.4結構性T1權重影像....... 18
2.4.1基於體素之形態學分析..22
2.5靜息態功能性磁振造影.... 25
2.5.1條件式種子功能性分析.. 27
2.5.2 大腦全局連結分析... 29
第三章 研究方法與材料
3.1實驗作業之主要流程...... 31
3.2健康受測者之收錄標準.... 32
3.3 COMT Val158Met基因型檢測...... 36
3.4磁振造影掃描之流程參數設定...... 37
3.5影像處理...... 39
3.6統計分析...... 46
第四章 研究成果
4.1人口統計學與認知分數.... 48
4.2各族群間大腦全局連結的變化趨勢..50
4.3各族群間視丘與大腦其他腦區之功能性連結的變化趨勢..52
4.4各族群間大腦局部灰質體積的變化趨勢.......54
4.5大腦功能及結構與認知分數之間的關聯性.....57
第五章 討論與結論
5.1 COMT Val158Met調控視丘隨著老化之大腦功能受到非線性效應所調控......60
5.2 COMT Val158Met調控視丘隨著老化之大腦結構受到非線性效應所調控......63
5.3 COMT Val158Met 在受多巴胺調節之大腦結構與功能的相反U型效應..64
5.4實驗限制......65
5.5未來展望......66
5.6結論..66

參考文獻

圖目次
圖2.1多巴胺傳導路徑示意圖..12
圖2.2 COMT基因之結構與其SNP位置示意圖......14
圖2.3單核甘酸變異多型性...15
圖2.4核磁共振基本原理示意圖........18
圖2.5 T1弛緩時間與T2弛緩時間說明圖..19
圖2.6 利用T1、T2突顯不同組織之對比..21
圖2.7 T1權重影像及T2權重影像...... 27
圖2.8 種子點功能性分析示意圖......29
圖2.9 GBC分析示意圖......31
圖3.1本實驗作業流程圖.....39
圖3.2 影像分析處理流程圖..45
圖3.3 DARTEL-based T1 VBM分析流程圖......46
圖3.4 統計分析之分組排列示意圖.....51
圖4.1 族群間於雙側視丘之GBC變化趨勢.52
圖4.2 族群間視丘與大腦其他腦區的FC變化趨勢..53
圖4.3 族群間於右腦視丘之GMV變化趨勢.55
圖4.4 族群間於右腦顳葉中端區之GMV變化趨勢...56
圖4.5 老年組受測者之右腦視丘GMV與GBC呈現負相關趨勢..57

表目次
表3.1 受測者基本資料......35
表3.2 磁振造影掃描參數....38
表4.1 各族群的人口特徵與認知分數...49
表4.2 大腦功能與結構之相關性分析...58
表4.3 視丘功能與結構之相關性分析...59


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