- 學位論文
大腦類澱粉血管病變之診斷與病態生理機轉之探討
Multimodal Diagnosis and Pathophysiology of Cerebral Amyloid Angiopathy
摘要
大腦類澱粉血管病變是一種β澱粉樣蛋白沈積在大腦皮質層和腦膜的小血管中引起的疾病，是自發性大葉型腦出血的主要病因。由於目前臨床治診斷方式侷限，對其致病機制也尚未了解，因此本研究包括三個具體目標，包括：（1）使用多重神經影像技術的方法研究大腦類澱粉血管病變的影像學特徵；（2）在同時患有大葉和深部出血（混合型腦出血）的患者中診斷大腦類澱粉血管病變；（3）建立血管間隙擴大與類澱粉血管病變之關聯性，並使用動物模型確定血管澱粉樣蛋白經由淋巴引流系統清除。 我們前瞻性地招募了症狀性腦出血的患者進行血液敏感性磁振造影和澱粉樣蛋白正子攝影檢查，以研究大腦類澱粉血管病變的影像學表現。我們發現，大腦澱粉樣血管病變不僅會導致大腦出血，也會導致小腦淺層微出血。我們同時建立了大腦類澱粉血管病變與腦葉裂隙性梗塞之間的關聯性，因此將此疾病的腦實質損傷從出血性表現擴展到了缺血性表現，這些影像標誌都可提高未來大腦類澱粉血管病變臨床診斷的敏感性。由於目前混合型腦出血的患者的致病原因還有所爭議，我們進一步利用澱粉樣蛋白正子攝影檢查，確認了他們主要的致病機轉是高血壓性小血管病變，而非大腦類澱粉血管病變。然而，一小部分混合型腦出血的病人同時患有兩種血管病變，而我們的兩年縱向追蹤資料證實了大腦類澱粉血管病變是其未來發生不良血管事件的危險因子，再次證明了在腦出血族群的患者中，診斷類澱粉血管病變的重要性。 為了進一步了解其致病機轉，我們在大腦類澱粉血管病變的病人中，研究磁振造影下可見的擴大血管周隙，發現其與澱粉樣蛋白沈積量增加有關。由於擴大的血管周隙暗示了大分子物質從大腦排除的淋巴引流功能受損，我們接著使用表現血管沈積澱粉樣蛋白的基因轉殖小鼠模型，破壞其腦膜淋巴引流途徑，發現會導致後續大腦的血管周隙擴大與血管澱粉樣蛋白沉積加劇，證實了腦膜淋巴引流是大腦類澱粉血管病變致病機轉的關鍵路徑，這也是未來發展大腦類澱粉血管病變治療策略的潛在標的。
並列摘要
Cerebral amyloid angiopathy (CAA) is caused by deposition of β-amyloid (Aβ) in the small vessels at cerebral cortex and overlying leptomeninges, and is the major etiology of spontaneous lobar intracerebral hemorrhage (ICH). Currently, the clinical diagnosis of CAA is mostly limited to hematoma location, and the underlying pathogenic mechanism is still poorly understood. This research is composed of three specific aims, including (1) investigate imaging features in CAA using a combined approach of multimodal neuroimaging techniques, (2) diagnose CAA in patients presenting with mixed lobar and deep hemorrhage (Mixed-ICH), and to understand their long-term outcomes, and (3) Establish the association between PVS and vascular amyloid burden, and determine whether vascular amyloid clearance is related to lymphatic drainage system using animal models. We recruited patients with symptomatic ICH for blood sensitive MRI and amyloid PET studies to investigate radiological presentation of CAA other than strictly supratentorial lobar bleeds. We discovered CAA can result in not only supratentorial, but also strictly superficial cerebellar microbleeds. We also established the association between CAA and supratentorial lobar lacunar infarct, and therefore extended the parenchymal injury from hemorrhagic to ischemic presentations. These markers may potentially improve the sensitivity in CAA clinical diagnosis. We further examined Mixed-ICH, a group of patients whose underlying small vessel disease are still controversial. Using in vivo amyloid PET, we confirmed they harbor mainly hypertensive microangiopathy but not CAA. However, a small group of patients had dual pathologies with coexisting CAA, and our 2-year longitudinal follow-up data indicated CAA is the risk factor for detrimental vascular outcome, re-enforcing the importance of CAA diagnosis in ICH population. To further understand the pathogenic mechanisms, we investigated MRI-visible enlarged perivascular space, a proposed radiological marker indicating impaired perivascular drainage function of macromolecules, and we showed it is related to increasing amyloid burden in CAA. We further compromised the meningeal lymphatic drainage route using transgenic mouse model of CAA, and demonstrated subsequently dilated perivascular space and exacerbated vascular amyloid deposition. Our results confirmed that the meningeal lymphatics is a crucial pathway in CAA pathogenesis and have translational potential for developing future therapeutic strategy.