Vascular Pathology in Early and Asymptomatic Cerebral Amyloid Angiopathy

项目摘要/摘要 脑淀粉样血管病(CAA)是一种与年龄相关的脑部小血管疾病，常见于 老年人。CAA在这一人群中导致了两种可能具有破坏性的主要结果：脑叶内 出血(ICH)和血管认知障碍和痴呆(VCID)。CAA的特点是 皮质和软脑膜动脉壁中β-淀粉样蛋白(A-β)的进行性沉积导致血管形成 功能障碍。血管功能障碍是CAA中常见的小血管病变的基础，如 大叶微出血(MB)和皮质浅铁质沉着症(CS)。除了表现出血管功能障碍外， 相当大比例的CAA患者存在典型的淀粉样斑块和tau基神经原纤维缠结 阿尔茨海默氏症的病理，这也可能影响疾病的进程。 尽管CAA通常在患者发展为脑叶脑出血或痴呆后被发现，但神经病理学 流行病学研究表明，早期的、但在病理上处于晚期的临床前CAA形式是 很普通。该项目在初始资金期产生的数据表明，在此之前 研究不足的患者现在可以使用基于MRI的生物标记物以高特异性可靠地识别。这个 关键的下一步是确定可能影响CAA早期病程的可改变的危险因素。 与其他形式的中风不同，预防CAA相关结局的可修改风险因素尚未得到 已确认身份。初步证据表明，在CAA合并脑叶出血的患者中，平均血压升高 (BP)预测脑出血复发的风险增加。新出现的证据表明，BP变异性增加与 脑小血管疾病、中风和痴呆症的风险增加超过平均血压的作用 级别。然而，目前尚不清楚血压变异性是否也与CAA的亚临床病程有关。 病人。在没有发生脑出血的早期CAA患者中，近三分之一的患者在两年内发展为痴呆症。 痴呆是由进行性血管功能障碍引起的，还是由tau或淀粉样蛋白引起的？我们的 初步数据表明，BP的变异性会影响tau的积累。潜在的生物机制 人们对此了解甚少。使用无脑出血病史的CAA患者的前瞻性队列，我们将 回答以下三个关键问题：1)以血压水平升高和 变异性，增加早期CAA患者出血事件的风险？2)血压是否影响 CAA相关血管或tau或淀粉样变？3)早期CAA患者的血压是否有影响 认知障碍和痴呆症的发展？

PROJECT SUMMARY/ABSTRACT Cerebral amyloid angiopathy (CAA) is an age-related cerebral small vessel disease that is common in elderly. CAA causes two principle, potentially devastating, outcomes in this population: lobar intracerebral hemorrhage (ICH) and vascular cognitive impairment and dementia (VCID). CAA is characterized by progressive deposition of β-amyloid (Aβ) in the walls of cortical and leptomeningeal arteries leading to vascular dysfunction. Vascular dysfunction underlies the lesions of small vessel disease typically seen in CAA such as lobar microbleeds (MB) and cortical superficial siderosis (cSS). In addition to exhibiting vascular dysfunction, a significant proportion of CAA patients harbor the amyloid plaques and tau-based neurofibrillary tangles typical of Alzheimer’s pathology which may also influence disease course. Although CAA is often identified in patients after they develop lobar ICH or dementia, neuropathological and epidemiologic studies suggest that early, yet pathologically advanced pre-clinical forms of CAA are common. Data generated from this project during the initial funding period have shown that these previously understudied patients can now be reliably identified with high specificity using MRI-based biomarkers. The critical next step is to identify modifiable risk factors that may influence early disease course in CAA. In contrast to other forms of stroke, modifiable risk factors to prevent CAA-related outcomes have not been identified. Preliminary evidence suggests that in CAA patients with lobar ICH, elevated mean blood pressure (BP) predicts increased risk of ICH recurrence. Emerging evidence has linked increased BP variability to elevated risk of cerebral small vessel disease, stroke and dementia above and beyond the role of mean BP levels. It is, however, unknown whether BP variability may also contribute to subclinical disease course in CAA patients. In early CAA patients who do not develop incident ICH, nearly a third develop dementia over 2 years. Is dementia caused by progressive vascular dysfunction or tau or amyloid pathology in the disease? Our preliminary data suggests that BP variability influences tau accumulation. The underlying biologic mechanisms are poorly understood. Using a prospective cohort of patients with CAA without previous history of ICH, we will answer the following three key questions: 1) Does abnormal BP, characterized by elevated BP level and variability, increase the risk of bleeding events in patients with early CAA? 2) Does BP affect progression of CAA-related vascular or tau or amyloid pathology? 3) In patients with early CAA does BP influence development of cognitive impairment and dementia?