使用多種磁振造影技術多方面評估阿茲海默症動物模式腦部血管型態及功能之變化

Abstract

中文摘要 在邁向老年化的世界中,阿茲海默症愈來愈備受重視,患有阿茲海默症病人 會漸漸的喪失記憶並出現語言情緒上的障礙,不論在家庭生活或社會上皆造成龐 大的負擔。由於此疾病無法治癒且形成的原因至今尚未明確,目前只能以藥物來 延緩病情。阿茲海默症惡化時智力逐漸喪失的症狀稱為失智(dementia),過去研究 指出,在此過程中患者的大腦中會出現類澱粉斑塊(beta-amyloid plaques)沈積以及 神經纖維糾結(Neurofibrillary Tangles,NFTs)現象。然而越來越多證據指出,腦 部微血管循環的衰退可能是阿茲海默症的主要成因之一[1]。本研究中希望能利用 多項磁振造影技術對於腦部血管變化上提供更多有價值的關鍵資訊。 阿茲海默症患者腦中,過去研究指出異常蛋白質沈積及腦中代謝狀態會相伴 改變,輸送往腦部的血流供應的變化,亦會引發一連串的生理變化[2]。在現今多 種生理觀測儀器中,核磁共振影像能以非侵入式的方法獲取多項生理性參數,更 能掃描高解析的解剖影像,是研究此症的一大利器。到目前為止鮮少有資料討論 阿茲海默症腦部的詳細血管變異情況,本論文係利用磁振造影中 3D-ΔR2-MRA 血 管造影技術,以全腦性且高解析的血管影像呈現整體腦部血管構造,再加上比較 腦部血流量(CBF)之差異以及輔助使用 MRS 來觀察腦中的代謝物質的改變,藉由 這些技術比較阿茲海默症大鼠模型和正常大鼠的大腦血管構造與大腦生理的變異, 並且對疾病模型投以目前臨床最常用的藥物愛憶欣(Aricept),觀察其藥物在大腦產 生之改變及其療效,進一步探討阿茲海默症、腦部血管與代謝物變化之間的關係。 本研究結果顯示,在阿茲海默症大鼠模型中,發現到腦部血流量較正常大鼠 下降約 40~50% (P<0.05),經過愛憶欣藥物治療後其測得的腦部血流量數值則較阿 i 茲海默症大鼠為高,其腦部血流數值約為正常大鼠的 80~85% (P<0.05),值得注意 的是,同時比較三組大鼠腦部容積方面,並無明顯差異,顯見腦部血流變異在解 剖型態改變前即發生。在磁振頻譜中同樣可以觀察到阿茲海默症大鼠的神經元活 動指標 N-acetyl aspartate(NAA) 較正常大鼠下降 10~20%(P<0.05),經過愛憶欣藥 物治療後其測得的腦部 NAA 含量同樣較阿茲海默症大鼠為高,但差異不明顯。而 使用 TOF-MRA 亦有同樣結果,在正常大鼠中使用 TOF-MRA 顯示血管末端分支 以及整體血管皆較阿茲海默症大鼠有較高的訊號,經過愛憶欣藥物治療大鼠則可 見到血管末端訊號同樣較阿茲海默症大鼠為高。最後在應用在 3D-ΔR2-MRA 血管 造影技術上,可看到在整體的小血管密度上,阿茲海默症狀大鼠同樣較正常大鼠 有較為稀疏的腦部皮質小血管分佈狀態,經由腦皮質血管密度定量結果亦同;正 常大鼠腦部皮質血管密度為 4.95%,阿茲海默症大鼠為 2.1%,藥物治療組為 2.9%, 在最後的腦染色切片中也可以看到大量的類澱粉斑塊散佈在腦實質當中。 總結本研究可以推斷;在阿茲海默症動物模型中,腦部的血管變異以及血流 是有變化的;包含明顯的腦血流量下降以及血管衰退情形。而藥物愛憶欣除了是 乙醯膽鹼酶抑制劑外,在本實驗顯示有增加血流量之功用。由此可以確定在阿茲 海默症中,腦部類澱粉斑塊的形成與血管變異是相伴出現的。經由多種磁振造影 技術的探測,可以在解剖影像出現變異前就偵測到腦部血管的變異,而回復血管 的功能以及血流量,也許是治療阿茲海默症的另一個途徑,同時也期望在臨床上 能提供在腦部型態變化前的一個鑑別診斷與治療策略更有價值的資訊。

ABSTRACT Towards increasing aging population in the modern society, the treatment of Alzheimer's disease (AD) patient is getting more important. Patients suffering from Alzheimer's disease will gradually lose memory capability and have language emotional barriers. This situation will cause a huge burden in both ones family or society. The only medical care one can apply is to use drugs to defer AD patient’s conditions due to the lack of understanding on its fundamental mechanism. The situation in the Alzheimer's disease that gradually lost intellectual deterioration is known as dementia. Studies indicated that in this process of the brain of a patient would be the deposition of beta-amyloid plaques and neurofibrillary Tangles of NFTs phenomenon. More and more evidences have shown that the recession of the brain microvascular circulation might be one of main factors causing Alzheimer's disease [1]. This study is to provide more valuable information taking advantage of various MRI techniques for vascular changes in the brain. In the brains of Alzheimer's patients, past research pointed out that there will be abnormal protein deposition, and the metabolic state of the brains are also accompanied by change in the blood supply to the brain [2]. In a variety of physiological observation instruments, MRI is a major modality in the study of this disease to obtain physiological parameters with high-resolution anatomical images. So far, there is little information discussing the variation of cerebral vasculature of the Alzheimer's disease in the literature. This thesis is to use the newly developed MRI 3D-ΔR2-MRA angiography to present the overall high-resolution images of the vascular nature of the whole brain. In addition to it, TOF-MRA(time-of-flight MR angiography), CBF(cerebral blood flow) and MRS(MR spectroscopy) are also employed to reveal the blood vessel structures, blood perfusion and associated metabolites change in the brain. Aricept, the most commonly used drugs for Alzheimer’s disease, are applied to explore the relationship between Alzheimer's disease, vascular brain metabolite changes. The results show that, in the AD rat model with no treatment, that blood flow to the brain is decreased by about 40 ~ 50% (P <0.05), and is 15~20%(P <0.05) in the Aricept treatment group. Notably, there is no significant difference in the brain volume at the three groups. This shows that the variations of the brain blood flow might occur before the anatomy changes. Neuronal activity indicators N-acetylaspartate (NAA) in the magnetic resonance spectrum decreased by 10 ~ 20% (P <0.05) in AD rats

iii compared with normal rats. The Aricept treatment will raise NAA slightly, but insignificantly. Similar results are also shown in the TOF-MRA. In the normal rats, the intensity of the overall vascular were higher than that of AD. For Aricept treated rats, the blood vessels signal also shows higher compared to AD rats. Finally, 3D-ΔR2-MRA angiography can visualize the relatively sparse distribution of small vessels hence the overall density of the brain cortex in the AD animals, with brain cortex vascular density of 4.95% for the normal group, 2.1% for the AD rats, and 2.9% for the drug treatment group. Spreads of amyloid plaques in the brain parenchyma can also be seen in the final brain stained sections. In Summary, brain structure and functional change of the blood vessels can be studied for AD rats using various MRI technologies. Our result suggests that MRI could provide more valuable information for clinical diagnosis as well as treatment strategies in the near future.