背景及目的:足夠的腦血流對於維持腦部的正常功能相當重要。血管阻塞造成急性局部腦血流不足是造成中風的原因。然而慢性腦血流不足對於腦部結構的改變以及認知功能的影響越來越受到重視。早期神經學症狀惡化常在腦中風病人身上發現並且與不良的預後有關。過去有研究指出細胞黏著因子可能參與了栓塞區域的病生理變化，然而它與腦血流的關係仍然不清楚。因此本研究將利用新的影像技術動脈自旋標記磁振影像(ASL perfusion MRI)來測量腦血流，並探討(1)在腦中風病患中，灌注-擴散加權影像不匹配與早期神經學症狀惡化的關係；(2)在輕微認知功能障礙病患中，慢性腦血流不足對於大腦結構的改變以及認知功能的影響；(3)細胞黏著因子與灌注-擴散加權影像不匹配以及慢性腦血流不足的關係。

研究方法:此研究將分別收錄腦中風以及輕微認知功能障礙病患。在腦中風發生後48小時內執行動脈自旋標記磁振影像來偵測灌注-擴散加權影像不匹配，美國國家衛生研究院腦中風量表以及巴氏量表用來評估入院時，症狀發生一星期後及一個月後的神經學症狀和日常生活功能。早期神經學症狀惡化的定義為中風發生一星期後美國國家衛生研究院腦中風量表惡化超過兩分或以上。在入院時以及症狀發生一星期後，細胞黏著因子包括(VCAM-1, ICAM-1以及 E-selectin)在血漿的濃度將被測量。在輕微認知功能障礙病患中，我們使用動脈自旋標記磁振影像來測量各區域的腦血流量並且評估病患的認知功能以及測量收錄時的細胞黏著因子濃度。

結果: 共收錄120急性腦中風病患，其中風位於大腦半球內。65位是小間隙梗塞，55位是血栓及栓塞性梗塞。血栓及栓塞性梗塞的病患合併有灌注-擴散加權影像不匹配者有較高早期神經學症狀惡化的風險。而血中VCAM-1的濃度較高與灌注-擴散加權影像不匹配者及早期神經學症狀惡化有關。另外也收錄了110位輕微認知功能障礙病患。腦血流不足與認知功能下降，內側顳葉萎縮以及白質病變增加有關。而血中VCAM-1的濃度與腦血流成反比關係尤其是在後側頂葉部分。

結論: 本研究顯示急性腦血流不足造成灌注-擴散加權影像不匹配及早期神經學症狀惡化以及慢性腦血流不足與認知功能下降，內側顳葉萎縮以及白質病變有關。而細胞黏著因子尤其是VCAM-1對於急性或慢性腦血流不足扮演了一定的角色。

Background and Purposes: Maintaining sufficient blood flow to the brain consistently is important to keep normal brain function. As we know, ischemic stroke is a common disease caused by acute impairment of focal cerebral perfusion due to vessel occlusion. However, attention has recently focused on the adverse effect of chronic cerebral hypoperfusion on brain structural changes and cognitive function. Early neurologic deterioration (END) is frequently observed and related to poor functional outcome in acute ischemic stroke, Cell adhesion molecules (CAMs) have been reported to involve the pathogenesis of cerebral ischemia, however, the association with cerebral perfusion has not been evaluated. In this thesis, Arterial spin labeling (ASL) MRI, a new imaging technique, was used to assess the cerebral perfusion. There were several purposes in this study. (1) To understand the association between perfusion-diffusion (PWI-DWI) mismatch and END in acute stroke. (2) To understand the association between chronic cerebral perfusion and brain structural change in mild cognitive impairment (MCI). (3) To evaluate the impact of CAMs on perfusion-diffusion mismatch in acute stroke and cerebral hypoperfusion in MCI.

Material and methods: The study separately enrolled acute stroke patients and patients with MCI. In acute stroke, ASL perfusion MRI was performed within 48 h of symptoms onset to detect PWI-DWI mismatch. National Institutes of Health Stroke Scale (NIHSS) and Barthel index were used to score neurologic deficit and functional impairment at admission, one week and one month after stroke. END was defined as an increase of 2 or more points in NIHSS within one week after stroke onset. Plasma levels of CAMs including VCAM-1, ICAM-1and E-selectin were measured at admission and one week after symptoms onset. In patients with MCI, ASL perfusion was used to quantitate regional cerebral perfusion. Cognitive function was assessed and plasma levels of CAMs were measured at enrollment.

Result: 120 patients with acute stroke in cerebral hemisphere were enrolled. There were 65 patients with lacunar stroke and 55 patients with thromboembolic stroke. Patients with PWI-DWI mismatch had higher risk for END in thromboembolic infarct. Higher level of VCAM-1 was independently associated with PWI-DWI mismatch and END in thromboembolic infarct. 110 patients with MCI were enrolled. Cerebral hypoperfusion was associated with cognitive impairment, medial temporal lobe atrophy and increase white matter lesions. The level of VCAM-1 was significant inversely associated with cerebral cortical perfusion especially posterior parietal lobe even after adjusted for cerebrovascular risk factors.

Conclusion: The study suggested the importance of cerebral perfusion as the PWI-DWI mismatch associated with END in acute stroke and chronic cerebral hypoperfusion associated with medial temporal lobe atrophy, white matter lesions and cognitive impairment in MCI. CAMs especially VCAM-1 played a role in acute and chronic cerebral hypoperfusion.

論文審定書 ...................................................................................................... i
誌謝 ………………………………........................................................................ ii
中文摘要......................................................................................................... iii
英文摘要......................................................................................................... iv

第一章 Introduction and purpose ..................................................................... 1
1.1 Cerebral perfusion ................................................................................... 1
1.2 Imaging of cerebral perfusion .................................................................... 1
1.3 Early neurologic deterioration in acute stroke ……...................................... 2
1.4 Cerebral perfusion in acute ischemic stroke .............................................. 3
1.5 Perfusion imaging and related findings in acute stroke ............................... 4
1.6 Cerebral perfusion in patients with mild cognitive impairment ...................... 6
1.7 Perfusion imaging and related findings in patients with MCI ........................ 7
1.7.1 Cerebral perfusion and cortical atrophy .................................................. 7
1.7.2 Cerebral perfusion and white matter lesions ........................................... 8
1.8 Roles of cell adhesion molecules ……………………................................... 8
1.8.1 Roles of cell adhesion molecules in acute stroke ................................... 9
1.8.2 Roles of cell adhesion molecules in dementia ........................................ 10
1.9 Rationale and aims of the study .............................................................. 11
1.9.1 Rationale and aims of the study in acute stroke ..................................... 11
1.9.1 Rationale and aims of the study in patients with MCI .............................. 12
第二章 Material and methods ........................................................................ 14
2.1 Patient enrolment ................................................................................... 14
2.1.1 Patients with acute ischemic stroke ...................................................... 14
2.1.2 Patients with mild cognitive impairment ................................................. 15
2.2 Cerebrovascular risk confounders ............................................................. 15
2.3 Plasma levels of cell adhesion molecules ................................................. 16
2.4 Clinical assessments .............................................................................. 17
2.4.1 Neurologic deficit and outcome evaluation in acute stroke ........................ 17
2.4.2 Cognitive assessment in patients with mild cognitive impairment .............. 17
2.5 Brain magnetic resonance imaging ........................................................... 17
2.5.1 Imaging acquisition .............................................................................. 17
2.5.2 Quantitative infarct volume and PWI-DWI mismatch ................................ 18
2.5.3 ASL perfusion MRI analysis in MCI ........................................................ 19
2.5.4 Gray matter atrophy using voxel-based morphometry .............................. 20
2.5.5 Automated gray matter volumetry .......................................................... 21
2.5.6 Assessment of white Matter Changes .................................................... 23
2.6 Statistical analysis ................................................................................. 24
3.6.1 In patients with acute stroke ................................................................. 24
3.6.2 In patients with MCI ............................................................................. 25
第三章 Results-in acute ischemic stroke ........................................................ 26
3.1 Demographic data and clinical characteristics in patients with lacunar and thromboembolic infarct ................................................................................................................... 26
3.2 Plasma levels of cell adhesion molecules in patients with lacunar and thromboembolic infarct ................................................................................................................... 26
3.3 Risk factors for early neurologic deterioration in all stroke patients .............. 26
3.4 Risk factors for early neurologic deterioration in thromboembolic stroke ...... 26
3.5 Predictors for PWI-DWI mismatch in thromboembolic stroke ..................... 27
第四章Results-in mild cognitive impairment .................................................... 35
4.1 Clinical characteristics of patients with MCI and its association with cerebral perfusion ................................................................................................................... 35
4.2 The association between VCAM-1 and regional cerebral perfusion ............... 35
4.3 The association between cerebral perfusion and cognitive function ............... 35
4.4 The association between cerebral perfusion and regional gray matter volume .................................................................................................................... 36
4.5 The association between global cerebral perfusion and white matter lesions .................................................................................................................... 36
第五章Discussion and conclusion .................................................................. 49
5.1 Main findings .......................................................................................... 49
5.2 In patients with acute ischemic stroke ....................................................... 49
5.2.1 Levels of CAMs in acute ischemic stroke ................................................ 49
5.2.2 PWI-DWI mismatch and early neurologic deterioration in thromboembolic stroke .................................................................................................................... 50
5.2.3 VCAM-1 and history of hypertension were associated with PWI-DWI mismatch in thromboembolic stroke .................................................................................................................... 50
5.2.4 Cell adhesion molecules and early neurologic deterioration ....................... 51
5.3 In patients with mild cognitive impairment ................................................... 53
5.3.1 The association between CAMs and cerebral perfusion ............................. 53
5.3.2 The association between cerebral hypoperfusion medial temporal atrophy ..................................................................................................................... 54
5.3.3 The association between cerebral perfusion and white matter lesions ..................................................................................................................... 55
5.3.4 The association between cerebral perfusion and cognitive function ............. 55
5.3.5 Other factors correlated with cerebral perfusion ………………................…. 56
5.4 Conclusion ............................................................................................ 56
第六章Technical considerations and possible limitation ..................................... 58
第七章Future direction ................................................................................... 60
參考文獻........................................................................................................ 62
附錄 . ......................................................................................................... 74

圖次
圖2-1 PWI-DWI mismatch and without match ................................................... 19
圖2-2 Process of ASL perfusion imaging ......................................................... 20
圖2-3 Process of grey matter .......................................................................... 21
圖2-4 Flowchart of IBASPM steps ................................................................... 22
圖2-5 Fazekas scale for WMLs ....................................................................... 24
圖3-1 Levels of cell adhesion molecules in patients with lacunar and thromboembolic infarct ..................................................................................................................... 30
圖4-1 Regions of cortical perfusion that were inversely correlated with levels of VCAM-1 ...................................................................................................................... 40
圖4-2 The correlation between VCAM-1 level and posterior-inferior parietal perfusion ..................................................................................................................... 41
圖4-3 Regions of perfusion that were correlated with short term memory score .... 43
圖4-4 The correlation between cerebral perfusion and cognition .......................... 44
圖4-5 Regions of gray matter volume correlated to global cerebral perfusion ........ 46
圖4-6 The correlation between medial temporal perfusion and medial temporal volume .................................................................................................................... 47



表次
表3-1 Clinical data in patients with lacunar and thromboembolic infarct............... 28
表3-2 Levels of cell adhesion molecules in patients with lacunar and thromboembolic infarct........................................................................................................... 29
表3-3 Factors associated with early neurologic deterioration in patients with acute ischemic stroke.......................................................................................................... 30
表3-4 Factors associated with early neurologic deterioration in patients with thromboembolic infarct........................................................................................................... 31
表3-5 Factors associated with PWI-DWI mismatch in patients with thromboembolic infarct........................................................................................................... 32
表3-6 Multivariate logistic regression analysis for possible factors associated with PWI-DWI mismatch .................................................................................................................... 33
表4-1 Clinical data of 110 patients with mild cognitive impairment and the correlation with global cerebral perfusion .................................................................................................................... 36
表4-2 Correlation between VCAM-1 and regional cerebral perfusion.................... 37
表4-3 Correlation between cerebral perfusion and cognitive function.................... 42
表4-4 Correlation between cerebral perfusion and gray matter atrophy................. 45
表4-5 Correlation between cerebral perfusion and white matter lesions................ 48

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