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研究生:林建源
研究生(外文):Chien-Yuan Lin
論文名稱:發展高解析度磁振灌流以及顯微血管造影技術:評估大腦新生血管功能及結構
論文名稱(外文):Development of High Resolution Magnetic Resonance Perfusion Imaging and Angiography Technique: Structural and Functional Assessment of Cerebral Angiogenesis
指導教授:陳志宏陳志宏引用關係
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:電機工程學研究所
學門:工程學門
學類:電資工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:111
中文關鍵詞:血管新生大腦血量血管滲透率缺血性中風對比劑穩態顯微血管造影
外文關鍵詞:AngiogenesisCerebral blood volumeVascular permeabilityIschemiaContrast agentSteady stateMicroscopy magnetic resonance angiography
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血管新生 (Angiogenesis) 在生物病理上,如腫瘤以及中風,扮演了重要的角色。新生的血管將提供細胞養分與能量,然而在腫瘤上過量的血管新生將促使腫瘤快速生長並轉移,因此若能有效的限制腫瘤血管新生,腫瘤的成長將可以有效的抑制。相反的,大腦因為血管阻塞所造成的組織缺氧,則需要大量的新生血管,若能適當的促進血管新生將可改善此類疾病所造成的組織傷害。因此,若有影像技術可以提供非侵入式來觀察組織病變區域血管新生的發展,並提供量化指標,對瞭解血管新生機制以及評估後續治療提供極大的助益。
近年來,動態對比加強磁振造影技術所提供的量化指標,如血流、血量、血液穿留時間等,已被廣泛用來分析血液動力機制,但是此技術牽涉到動態造影,無法提供高解析度影像分析。穩態對比增加磁振造影技術 (Steady-State Contrast-Enhanced MRI, SSCE-MRI)藉由獲取一組注射氧化鐵對比劑前後的高解析度影像來計算血管內因為氧化鐵對比劑存在所造成的橫向弛豫時間改變,包含以自旋迴訊為主的ΔR2以及梯度迴訊為主的ΔR2*。ΔR2值對於小血管血量敏感,而ΔR2*對於大小血管的血量皆敏感。從這兩者可進一步得到血管管徑(ΔR2*/ΔR2)與密度(ΔR2/(ΔR2*)2/3)的資訊。這些技術的發展可讓我們對於新生血管在功能性及結構性於疾病中的演變做更深入的探討。
本篇論文之目的主要是發展以及應用進階灌流造影技術來分析血管新生。第一部份研究是應用動態以及穩態對比加強磁振影像技術來分析由缺血性中風所引發的血管新生而造成血液動力機制上的改變,並透過組織切片染色來進一步確認結果。第二部分研究則是有鑑於現行的血管造影方法主要觀測大動脈以及大靜脈,對小於80μm的小動脈以及小靜脈則無法呈像,因而發展新型顯微血管磁振造影技術來觀察血管結構因為血管新生的演變過程。
從第一部份的研究中發現到在腦部局部缺血重新暢通後的3天至21天血管通透性逐漸上升,尤其在表層的皮質區域,腦血量也在3天至14天有明顯的增加,在微血管血量方面則在7天至14天上升。同時,從影像上發現在早期(1天至3天)血管密度下降,血管尺寸變大,這些血管結構上改變也進一步由免疫組織染色結果確認。總結而言早期的血量增加是由於血管側枝循環改善所造成,後期(5天至14天)的血量增加則是因為血管增生。
第二部分的研究,發展了ΔR2參數為主的三維顯微血管磁振造影技術。由結果發現這項技術以自旋回迅的delta R2參數為主,在小血管區域有很高的靈敏度,除了提供血管結構的資訊,也可反應血量的變化並且擁有較少的血管外相角發散以及由磁場不均勻所造成的影像扭曲。因此非常適合用於全腦微小血管造影。這項技術進一步用於觀察腦中風所引發的血管新生,發現較多的血管訊號產生於中風側,結果與第一部份研究相符合。
總結而言,本篇論文應用以及發展進階灌流造影技術來研究血管因病理而造成功能及結構上的改變,這對瞭解病理所造成的血液動力機制改變將有很大的助益。
The hemodynamic parameters such as vascular permeability, blood volume (BV), blood flow, and mean transient time obtained by dynamic magnetic resonance imaging with the utilization of contrast agent, have been widely used to study vascular remodeling in pathological tissue. However, these parameters obtained from the dynamic imaging technique require rapid imaging technique that severely compromises the spatial resolution. In addition, these parameters such as BV have been used to link the vessel density. It alone may not be a reliable indicator of microvessel density because the BV change reflects the combined effect on the average size and density of microvessels. Alternatively, steady-state contrast-enhanced magnetic resonance imaging (SSCE-MRI) with calculating the transverse relaxation rate shift in blood vessel due to the presence of the contrast agent has been proposed to study the microvasculature of pathological tissue. The gradient echo-based ΔR2* map reflects the BV changes in a broad range of vessel sizes, while the spin echo-based ΔR2 map reflects BV changes primarily in small vessels (e.g. capillaries and venules). These two parameters can be further derived to provide information on vessel size (ΔR2* /ΔR2) and density (ΔR2/(ΔR2*)2/3).
The purpose of this dissertation is to develop and validate the advanced perfusion MRI techniques to study angiogenesis. It is divided into two parts. First, we apply the dynamic contrast enhanced MRI (DCE-MRI) and SSCE-MRI techniques to investigate the postischemic change of vascular permeability, cerebral BV (CBV), vessel size and density in relation to evolving ischemia-induced angiogenesis over the course of 3 weeks, in a well-defined three-vessel occlusion model in the rat and the results were validated by immunohistology. Second, since the current angiographic methods of visualizing blood vessels in the clinical setting are excellent for evaluating larger arteries and veins but not the small vessels such as arterioles and venules, we developed a CBV-based microscopic magnetic resonance angiography technique, termed 3DΔR2-mMRA, which can simultaneously provide high-resolution 3D information on the cerebral anatomy, in vivo microvascular architecture, and hemodynamic response.
Several findings are interesting and valuable in our results. First, we reported a prolonged increase in vascular permeability from day 3 to day 21 postischemia, in particular the reperfused outer cortical layers and leptomeninges. Increased CBV was observed from day 3 to day 14, whereas increased CBV in small vessels, primarily capillaries, was noticed from day 7 to day 14, in the reperfused cortex. An initial drop in vascular density and a reciprocal increase in vessel size were observed within the reperfused cortex at day 1 and day 3 postischemia. Immunohistological analysis confirmed a similar decrease in microvessel density and increase in vessel size. Second, proposed microscopy MRA method with the advantage of less geometric artifacts can depict small vessels and trace individual vessel in normal and pathological tissue.
In summary, this dissertation successfully demonstrated the ability of SSCE-MRI and 3DΔR2-mMRA can provide the information of microvascular structure and function that may be useful to understand hemodynamic mechanisms of cerebro-vascular diseases and in assessing the efficacy of therapeutic strategies directed at angiogenesis.
Title Page 1
Acknowledgement 3
Chinese Abstracts 5
English Abstracts 7
Contents 9
List of Tables 12
List of Figures 13

Chapter 1 Introduction
1.1 The development of new blood vessel 15
1.1.1 Blood vessel development in the normal brain 15
1.1.2 Brain ischemia-induced angiogenesis 17
1.1.3 Tumour angiogenesis 18
1.2 Angiogenesis assessment 20
1.2.1 Dynamic MR imaging with contrast agent 21
1.2.2 Steady-State Contrast-Enhanced MRI (SSCE-MRI) 24
1.2.3 Magnetic resonance angiography 26
1.3 Motivation and Purposes 28
1.4 Outline 28

Chapter 2
Dynamic Changes in Vascular Permeability, Cerebral Blood Volume, Vascular Density and Size after Transient Focal Cerebral Ischemia in Rats: Evaluation with Contrast-Enhanced Magnetic Resonance Imaging
2.1 Introduction 30
2.2 Material and Methods 32
2.2.1 Stroke Model 32
2.2.2 MRI Experiments 33
2.2.3 DCE-MRI: Measurement of Vascular Permeability (Ktrans) 33
2.2.4 SSCE-MRI: Assessment of ΔR2, ΔR2*, Vascular Density and Size 34
2.2.5 Data Analyses 34
2.2.6 Immunohistological Analysis of Vascular Density and Size 35
2.2.7 Statistic analysis 36
2.3 Results 36
2.3.1 Changes of permeability (Ktrans) over time after transient ischemia 36
2.3.2 Relative blood volume changes in large vessels (ΔR2*) and small vessels (ΔR2) over time 37
2.3.3 Relative cerebral vascular density (Q) and size (ΔR2*/ΔR2) changes over time 38
2.3.4 Immunohistological Analysis of Vascular Density and Size 39
2.4 Discussion 40
2.4.1 Ktrans and BBB breakdown 40
2.4.2 CBV changes vs. ΔR2 and ΔR2* 41
2.4.3 Vessel density and size vs. Q and VSI 42
2.5 Conclusion 45

Chapter 3
In vivo Cerebromicrovasculatural Visualization using 3D ΔR2-based Microscopy of Magnetic Resonance Angiography (3DΔR2-mMRA)
3.1 Introduction 53
3.2 Material and Method 55
3.2.1 Transverse relaxation rate change in spin-echo (ΔR2) and regional CBV 55
3.2.2 Stroke model 56
3.2.3 Data acquisition 56
3.2.4 Data analysis 57
3.3 Results 58
3.3.1 Cerebromicrovasculatural visualization using 3DΔR2-mMRA 58
3.3.2 MRA method Comparison between TOF-MRA and 3DΔR2-mMRA 59
3.3.3 The visualization of ischemia-induced angiogenesis 59
3.4 Discussions 60
3.4.1 MRA methods comparison 61
3.4.2 The capability of proposed method to trace angiogenesis 63
3.4.3 The accuracy of ΔR2 value quantification 64
3.4.4 The challenge of proposed method for clinical use 65
3.5 Conclusion 66

Chapter 4 Discussions and Conclusion
4.1 Discussion 76
4.1.1 Contrast agent 76
4.1.2 SSCE-MRI methodology 77
4.1.3 Three-dimensional ΔR2 microscopy MRA 78
4.2 Conclusion 81
4.3 Future Works 82
4.3.1 The development of new contrast agent for 3DΔR2-mMRA 82
4.3.2 Temporal visualization of tumour angiogenic activity 82
4.3.3 Molecular imaging of the microvasculature 83

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