2017-08-012024-05-16https://scholars.lib.ntu.edu.tw/handle/123456789/666609摘要：腦出血約佔所有腦中風的四分之一，其病因除高血壓性腦出血外，大腦類澱粉血管病變(cerebral amyloid angiopathy，CAA)在年長者為一重要的致病因素。自2014 年台大神經部、影像醫學部及核子醫學部開始成立團隊，希望將來能對CAA 的診斷標準與致病因子有更深入的了解。據我們所知，目前在台灣並沒有其他研究CAA 的團隊。CAA 患者的大腦血管發生了異常的類澱粉沈積，影響了血管的正常結構而容易造成大腦出血，其典型的出血位置位於大腦皮質及下皮質區域，由於CAA 確切診斷需靠腦血管病理切片分析，故實際臨床上，若有年長者發生大腦皮質及下皮質區域腦出血，便推測可能為CAA 相關之腦出血，但該診斷其實常缺乏客觀的直接證據。核磁共振造影之SWI sequence可見大腦之微小出血點 (microbleeds)，然而這也只能間接幫助診斷。近年來所發展的類澱粉正子攝影 (amyloid PET)，可用以偵測腦部類澱粉的沈積，尤其常應用於有高度類澱粉沈積的阿茲海默失智症患者。於CAA 之臨床診斷，最近曾有研究顯示CAA 病患之大腦amyloid PET 訊號呈現均勻的升高，且訊號增加的分布形態和阿茲海默失智症不同。此外亦有研究嘗試以amyloid PET 應用於CAA 病患的臨床追蹤及治療，發現大腦amyloid PET 訊號可用以預測未來腦出血的位置及預測使用血栓溶解治療是否會發生出血性併發症。然而amyloid PET 於CAA 的診斷應用上仍有其瓶頸，如CAA 病患的amyloidPET 影像和正常人或阿茲海默失智症患者相比有時仍無法完全區分；而amyloid PET 於CAA的臨床應用還有許多領域尚待研究，如CAA和藥物引發出血性併發症之間的關係、臨床CAA目前診斷條件下的正確和錯誤情形及CAA 之類澱粉沈積之長期進展和變化等。另外Tau 蛋白也被認為是CAA 的可能致病機轉之一，Tau PET 運用在CAA 尚未被研究過。此外，運用新興免疫磁場分析 (immunomagnetic reduction, IMR) 可以準確定量血漿中微量的Aβ40、Aβ42、total tau 和phosphorylated tau 等，加上ApoE 基因的定序，本計畫目的在結合基因、分子生物及影像標誌，運用在:1. 提高 CAA 的診斷能力及效益2. 研究及了解 CAA 之生物及病理機轉3. 研究 CAA 患者類澱粉蛋白在血管沉積之長期進展和變化4. 找出預後的預測因子<br> Abstract: Intracranial hemorrhage (ICH) consists of about a quarter of stroke subtype. For elderly, cerebralamyloid angiopathy (CAA) is a common etiology of ICH. In National Taiwan University Hospital, we haveestablished a CAA team including neurologists, radiologists and nuclear medicine physicians since 2014. Wehope to go deep into the diagnosis and pathophysiology of CAA. To the best of our knowledge, there is noother CAA team in Taiwan.In patients with CAA, abnormal beta amyloid protein diffusely deposits at cerebral vasculatures, whichdisrupts the normal vessel structure and increases the risk of bleeding. The standard diagnosis for CAArequires pathological evidences of amyloid deposition at cerebral arteries. Clinically, a diagnosis ofCAA-related ICH is usually only made in an elderly developing cortical or subcortical lobar ICH withoutundergoing biopsy. Brain images using the SWI sequence of MRI study may show lobar microbleeds inpatients with CAA. However, there is still no direct and precise non-invasive diagnostic tool for CAA untilnow.Amyloid PET, using 11C-PiB to image amyloid burden, has been used for detecting the cerebralamyloid protein deposition in patients with Alzheimer’s dementia (AD) for years. Recently, amyloidPET has also been applied in the diagnosis of CAA. CAA patients showed diffusely increased globalPiB retention as compared to control subjects and the distribution of PiB retention is also differentfrom that seen in patients with AD in general. Nevertheless, the applications of amyloid PET in CAAdiagnosis are still not well established and many important issues still need to be extensively addressed.Furthermore, tau PET has emerged as a potential molecular imaging marker for SVD. Tau PETprovides a noninvasive method for measuring brain tau load. The correlation of tau PET findings inpatients with CAA has not been investigated before.In addition, ApoE gene has been reported to be risk factor for sporadic CAA as well as AD.Biochemical biomarkers, such as the levels of Aβ40 and Aβ42, also help us understand thepathophysiology of CAA. Recently, immunomagnetic reduction (IMR) assay, using bio-functionalizedmagnetic nanoparticles, has been proved to be a sensitive and accurate tool for the detection of thesebiological molecules.By combination of plasma (Aβ40, Aβ42, total tau, and phosphorylated tau, etc.), genetic (ApoE ε2or ε4 allele), MRI (cerebral perfusion, microbleeds, cortical superficial siderosis, enlarged perivascularspace, etc.) and PET imaging (amyloid and tau) biomarkers, the study aims to1. Enhance the diagnostic potentials of the radiological biomarkers by combining MRI and amyloidPET in CAA patients.2. Investigate the biological pathogenesis in CAA patients using the less invasive plasma biomarkersand to correlate with structural and function imaging, including MRI, amyloid and tau imaging.3. Study the characteristics of long-term progression of amyloid deposition in CAA patients using theradiological, biochemical and genetic biomarkers.4. Study the prognosis predicting markers.腦中風腦出血大腦類澱粉血管病變磁振造影類澱粉正子攝影tau 正子攝影Aβ 蛋白ApoE 基因Strokeintracerebral hemorrhagecerebral amyloid angiopathyamyloid PETtau PETMRIAβApoE