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研究生:黃建翔
研究生(外文):Chien-Hsiang Huang
論文名稱:以高解析度磁振造影技術評估缺血性中風後大腦血管結構與功能
論文名稱(外文):High-Resolution Structural and Functional Assessments of Cerebral Microvasculature after Cerebral Ischemia by Magnetic Resonance Imaging
指導教授:趙福杉
指導教授(外文):Fu-Shan Jaw
口試委員:陳儀莊張維典黃國書洪東源黃基礎郭德盛
口試委員(外文):Yijuang ChernWei-Tien ChangGuo-Shu HuangDueng-Yuan HuengJi-Chuu HwangDe-Sheng Guo
口試日期:2015-07-15
學位類別:博士
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:2015
畢業學年度:103
語文別:英文
論文頁數:85
中文關鍵詞:缺血性中風血管重塑血管結構血管功能血氧加權磁振造影
外文關鍵詞:cerebral ischemiavascular remodelingvascular structurevascular functionBOLD MRI
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血管重塑是對於缺血性中風後受影響組織的回復之重要機制。目前中風後的治療主要藉由促進血管新生改善組織受到的傷害。因此,了解腦中微小血管的結構和功能變化或許能夠對於為中風建立新穎的血管新生療法有幫助。本論文之目的為利用無顯影劑之血氧加權磁振造影(BOLD MRI)取得血管結構和功能,包含方法的發展及應用兩部份。第一部份為發展同時取得相對腦血容積和對微小血管成像的方法(3D gas ΔR2*-mMRA),第二部分則是運用現有技術探討血管擴張能力和氧化能力在血管新生前之變化。
在第一部份研究提出之3D gas ΔR2*-mMRA方法藉由吸入空氣至碳合氣(carbogen,含5%二氧化碳和95%氧氣)所造成之梯度遲緩時間改變(ΔR2*)取得相對腦血容積和對微小血管成像。利用3D gas ΔR2*-mMRA觀察血管之優點包含可從空氣和組織之交界區分出血管、血管對組織的對比高、不受血腦障壁受損之影響。在一中風大鼠動物模型中,3D gas ΔR2*-mMRA展示其在中風後第三天取得血管資訊之能力。然而,此技術在應用時須考慮主要呈現的血管為血氧濃度較低的靜脈以及因磁透率造成觀察到的血管被放大之限制。
第二部份,我們在中風大鼠動物模型中使用二氧化碳刺激之血氧加權反應評估血管擴張能力,並用氧氣刺激之血氧加權反應搭配組織氧加權(TOLD)反應評估血管氧化能力。本論文中血管擴張能力定義為血管對於血碳酸壓力升高而產生擴張之能力,血管氧化能力則為血管對於血氧壓力升高而提升血氧飽和度之能力。在梯度迴訊映像的靜脈血管影像上,第一天並未發現血管形狀之訊號,而其在第三和七天出現。第三和七天的高二氧化碳刺激之血氧加權反應則指出這些區域有很高的血管擴張能力。在時序上血管擴張能力和肌間線蛋白(desmin)組織染色的高相關性指出血管擴張能力與周細胞(pericyte)之覆蓋率有關,而此由血管內皮生長因子(VEGF)所調控。氧氣刺激在第一、三和七天皆引起微小的血氧加權反應和巨大的組織氧加權反應,代表著缺血後組織的氧氣消耗少而血管氧化能力低。
本論文中的3D gas ΔR2*-mMRA方法建立以及缺血性中風後血管擴張能力和氧化能力之觀察,或許能提供對於中風後微小血管結構及功能之改變有更進一步了解之機會。


Vascular remodeling is an important mechanism to rescue the affected tissues after ischemia. Current therapies for stroke base on amplifying the angiogenesis. Understanding the structural and functional changes of the cerebral microvasculature may facilitate the development of the novel angiogenic therapies for stroke. The purpose of this dissertation is to use gas-challenged blood oxygen level-dependent (BOLD) MRI to assess the vascular structure and function. There are two parts in this dissertation. The first part is to develop a new method that simultaneously visualizes the cerebral microvasculature and obtains relative cerebral blood volume (rCBV). The second part is to apply the previously developed approach to investigate the vascular reactivity (VR) and functionality (VF) at the proangiogenic stage after ischemia.
In the first part, the new method of 3D gas-challenged ΔR2*-based microscopic MRA (3D gas ΔR2*-mMRA) utilizes gas-challenged BOLD contrast to assess rCBV and directly visualize the morphology of cerebral microvasculature in rat brains. The advantages of using 3D gas ΔR2*-mMRA to observe the microvasculature include the ability to distinguish air–tissue interfaces, a high vessel-to-tissue contrast, and not being affected by damage to the blood–brain barrier. A rat model of transient focal cerebral ischemia was used to demonstrate the ability of 3D gas ΔR2*-mMRA to provide information about poststroke revascularization at 3 days after reperfusion. However, this technique has some limitations that cannot be overcome and hence should be considered when it is applied, such as predominantly revealing venous vessels and magnifying vessel sizes due to the susceptibility effects.
In the second part, using the rat stroke model, the hypercapnic BOLD response was used to evaluate VR, while the hyperoxic BOLD and tissue oxygen level-dependent (TOLD) responses were used to evaluate the VF at 1, 3, and 7 days after ischemia. VR is defined as the ability of the vasculature to dilate in response to an elevated partial pressure of carbon dioxide level in this dissertation. VF is defined as the ability of the vasculature to increase oxygen saturation in response to an elevated partial pressure of oxygen level. Vessel-like venous signals appeared on R2* maps on days 3 and 7, but not on day 1. The large hypercapnic BOLD responses on days 3 and 7 indicated that these areas have high VR. The temporal correlation between VR and the immunoreactivity to desmin and VEGF further indicates that the integrity of VR is associated with the pericyte coverage as regulated by the VEGF level. VF remained low on days 1, 3, and 7, as reflected by the small hyperoxic BOLD and large hyperoxic TOLD responses, indicating the low oxygen consumption of the ischemic tissues.
The method development of 3D gas ΔR2*-mMRA and the investigations of VR and VF after ischemia in this dissertation may offer the opportunity to thoroughly understand both the structural and functional characteristics of microvascular alterations after ischemia.


致謝 i
中文摘要 ii
Abstract iv
Chapter 1 Introduction
1.1 The structure and function of the cerebral microvasculature after ischemia 1
1.2 Magnetic resonance imaging (MRI) for assessments of vascular structure and function 3
1.2.1 MRI vascular assessments with contrast agent (CA) 3
1.2.2 MRI vascular assessments without CA 6
1.3 Motivation and Purposes 8
Chapter 2
High-resolution structural and functional assessments of cerebral microvasculature using 3D gas-challenged ΔR2*-based microscopic MRA (3D gas ΔR2*-mMRA)
2.1 Introduction 9
2.2 Theory 11
2.3 Materials and Methods 12
2.3.1 Subjects 12
2.3.2 Stroke model for studying poststroke revascularization 12
2.3.3 Blood gas, blood pressure, and oxygen saturation measurements 13
2.3.4 MRI experiments 13
2.3.5 Use of ΔR2* maps to reconstruct 3D gas ΔR2*-mMRA 14
2.3.6 MRI data analysis 14
2.3.7 Latex perfusion 15
2.4 Results 15
2.4.1 The choice of optimal BOLD contrast by gas challenges 15
2.4.2 Use of ΔR2* maps to reconstruct 3D gas ΔR2*-mMRA 16
2.4.3 Comparison of 3D gas ΔR2*-mMRA and MR venography 17
2.4.4 Comparison of 3D gas ΔR2*-mMRA and 3D ΔR2-mMRA 17
2.4.5 Application of 3D gas ΔR2*-mMRA to study poststroke revascularization 18
2.5 Discussion 18
2.5.1 The characterization of 3D gas ΔR2*-mMRA 18
2.5.2 Comparison of 3D gas ΔR2*-mMRA and MRA with contrast agents 19
2.5.3 The choice of the gases 20
2.5.4 The concern of acquisition time 21
2.5.5 Comparison of 3D gas ΔR2*-mMRA and MR venography 21
2.5.6 The visualized vessel size 22
Chapter 3
Temporal Assessment of Vascular Reactivity and Functionality using MRI during Postischemic Proangiogenenic Vascular Remodeling
3.1 Introduction 33
3.2 Materials and Methods 35
3.2.1 Stroke Model 35
3.2.2 MRI Experiments 35
3.2.3 Data Analysis 37
3.2.4 Immunohistological analysis 38
3.2.5 Statistical Analysis 38
3.3 Results 39
3.3.1 Temporal changes on T2WIs, DWIs, and R2* maps 39
3.3.2 Temporal changes in hypercapnic BOLD response 40
3.3.3 Temporal changes in hyperoxic BOLD response 40
3.3.4 Temporal changes in hyperoxic TOLD response 41
3.3.5 Immunohistochemistry of the vessel density, pericyte coverage, and vascular remodeling 41
3.3.6 Correlation among the MRI parameters and immunohistological data 42
3.4 Discussion 42
3.4.1 The findings of this study 42
3.4.2 Vascular reactivity after ischemia 42
3.4.3 Vascular functionality after ischemia 44
3.4.4 Experimental challenges 45
3.4.5 Conclusion 46
Chapter 4
Discussion and Conclusion
4.1 Discussion 55
4.1.1 Structural assessment of the cerebral microvasculature 55
4.1.2 Functional assessment of the cerebral microvasculature 56
4.2 Conclusion 57
4.3 Future work 58
Reference 68
Abbreviation 81
Honors and Publications 83


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