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研究生:沈廷馨
研究生(外文):Elise Ting-Hsin Shen
論文名稱:應用擴散磁振造影技術探討阿茲海默動物模型腦部結構性連結的進程與深腦電刺激治療潛力
論文名稱(外文):Diffusion MR Imaging Progression of Structural Connectivity and Therapeutic Potential of Deep Brain Stimulation in Alzheimer’s Disease Model
指導教授:趙福杉陳右穎陳右穎引用關係
指導教授(外文):Fu-Shan JawYou-Yin Chen
口試日期:2017-06-02
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學工程學研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:英文
論文頁數:44
中文關鍵詞:阿茲海默症深腦電刺激擴散磁振造影穹窿磁振相容探針
外文關鍵詞:Alzheimer’s diseasedeep brain stimulationdiffusion magnetic resonance imagingfornixmagnetic resonance compatible probe
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阿茲海默症是少數無法治癒、預防、減緩的主要死因之一。隨著平均壽命增加,此疾病的盛行率也隨之增加。深腦電刺激藉由增強或阻斷不同腦區之前連結已被證實可治療多種神經疾病。穹窿因為與海馬迴之間的連結,因此有希望為深腦電刺激的目標腦區來治療阿茲海默症。儘管目前已經有研究及試驗,但尚未真正了解深腦電刺激穹窿使阿茲海默症病人有正向表現的原因。在此研究中,使用阿茲海默症基因轉殖老鼠模型及擴散磁振造影技術來了解白質在疾病中的長期變化。阿茲海默症老鼠模型在約年紀六個月時,減少非等向性指標及行為的表現。透過磁振相容探針及動物模型,觀察到深腦電刺激的時機使治療成果上有所差異。阿茲海默症老鼠模型在穹窿進行深腦電刺激對於非等向性指標及行為表現上有改善。
Alzheimer’s disease (AD) is one of the major causes of death that currently cannot be cured, prevented, or slowed. Due to the rising survival age, the upward trend of the disease prevalence will continue. Deep brain stimulation (DBS) has proven to be a viable therapy for various neurological disorders, by enhancing or interrupting different connections within the brain. Various brain structures have been considered as the target for DBS, including the fornix. DBS of the fornix, a major output tract of the hippocampus, has been shown to be a promising target for DBS therapy in AD patients. Even though these studies and trials are taking place, it is still not well understood what alterations are resulting in positive changes within AD patients. In this study, a triple-transgenic (3xTg) mouse model of AD was used in order to understand the longitudinal changes of white matter over the course of the disease through the use of diffusion tensor imaging (DTI). The 3xTg mouse model showed to have decreased FA values and behavioral performance around the age of 6 months. Through the integration of a MR compatible probe and the 3xTg model, it was observed that the timing of the implantation of DBS stimulation probes and stimulation therapy makes a difference in the effectiveness of the therapy. DBS of the fornix showed improvement in the behavior of 3xTg mice and FA values.
Table of Contents
Acknowledgements i
摘要 ii
Abstract iii
Table of Contents iv
List of Figures vii
List of Tables viii
Chapter 1. Introduction 1
1.1 Alzheimer’s Disease 1
1.2 Deep Brain Stimulation 4
1.3 Fornix, Papez Circuit, and Limbic System 5
1.4 Deep Brain Stimulation Targets Considered for Alzheimer’s Disease 6
1.5 Deep Brain Stimulation of the Fornix in Alzheimer’s Disease 6
1.6 Diffusion Tensor Imaging 7
1.7 Motivation and Objectives 8
Chapter 2. Materials and Methods 9
2.1 Experimental Design 9
2.2 Animal Models 9
2.3 Genotyping of 3xTg AD Mice 11
2.4 Immunohistochemistry 11
2.5 Surgical Techniques 12
2.6 Stimulation Parameters 13
2.7 Novel Object Recognition 13
2.8 Magnetic Resonance Imaging Procedures 15
2.9 Diffusion Tensor Imaging Analysis: Tractography Based Spatial Statistics 16
2.10 Selection of Regions of Interest and Analysis 17
Chapter 3. Results 20
3.1 Amyloid Beta in Alzheimer’s Triple Transgenic Mouse Model 20
3.2 Neural Probe MR Compatibility 20
3.3 Long-term Connectivity Progression Fractional Anistropy of Alzheimer’s Disease 3xTg Mouse Model 22
3.4 Fractional Anistropy Changes from Deep Brain Stimulation in the Fornix 23
3.5 Regions of Interest Fractional Anistropy Changes in 3xTg Mice without DBS Therapy 24
3.6 DTI Value Changes in 3xTg AD Mice after Fornix DBS 24
3.7 Deep Brain Stimulation in Different Alzheimer’s Disease Stages 26
3.8 Novel Object Recognition 26
Chapter 4. Discussion 29
4.1 Structural Changes Throughout Alzheimer’s 29
4.2 Applicability of Deep Brain Stimulation for Alzheimer’s Disease 29
4.3 Effectiveness of Fornix Deep Brain Stimulation on Different Disease Stages 30
4.4 Cognitive Enhancement in NOR Performance Post-DBS 31
4.5 Proposed Circuitry Change from Fornix Deep Brain Stimulation 32
4.6 Translating Mouse Model Studies to Human Clinical Applications 33
4.7 Future Works 33
Chapter 5. Conclusion 36
References 37
Appendix 41
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