Extracranial Carotid Atherosclerosis Contributions to Cognitive Impairment and Alzheimer's Disease Risk

项目总结/摘要 越来越需要了解与血管贡献相关的机制和治疗方案 阿尔茨海默病（AD）和其他形式的痴呆症和认知功能障碍。早期大脑变化 与AD和其他形式的认知功能障碍相关，例如白色病变（WML）负担， 低灌注和代谢不匹配具有血管危险因素（高血压、糖尿病、衰老和吸烟）。 这种脑结构和功能的变化通常被认为是继发于颅内脑小血管 疾病相反，我们的初步数据表明，颅外颈动脉疾病（ECAD）有助于 脑病理学及其颈动脉内膜切除术（CEA）治疗（手术切除斑块） 减少WML和神经元缠结的积累，增加结构连接， 更重要的是，提高认知能力。 ECAD主要是指颈动脉分叉处的动脉粥样硬化，其中斑块积聚是唯一的 与其他脑血管部位相比更为普遍。颈动脉在大脑生理学中起着重要作用 因为它们将大部分血液和营养物质输送到大脑。我们假设ECAD的机制 阿尔茨海默病和认知功能障碍可能是多因素的， 现象、血流减少和内皮活化/炎症。这些可修改的 因素和不可改变的风险（即年龄，性别和ApoE状态）可能导致神经退行性变， 导致认知功能障碍。我们的目标1和2使用横断面研究来评估 ECAD对AD相关脑结构和功能改变的贡献。受试者评价包括 神经认知测试和MRI定义的结构参数的量化，WML积累，阿尔茨海默氏症 基于血液的疾病生物标志物，以及炎症的全身、脑和颈动脉标志物。Aim 3采用了 一项前瞻性对照队列研究，评价CEA治疗ECAD，以确定哪些患者 显示出改善的认知功能（反应者），以及什么因素是这种反应的驱动因素。 该项目将定义导致神经退行性变的大脑结构变化的量化措施， ECAD患者的认知功能障碍。这将进一步推动临床试验的变革 管理ECAD患者。此外，我们的研究提供了一个令人兴奋的机会， 早期阿尔茨海默病的风险和血管贡献的具体机制。了解独特的 ECAD对AD/认知功能障碍风险的贡献特别引人注目，因为有效 存在ECAD的治疗方法，但目前还没有提供用于治疗/预防认知功能障碍的治疗方法。 功能障碍

PROJECT SUMMARY/ABSTRACT There is growing need to understand mechanisms and treatment options associated with vascular contributions to Alzheimer’s disease (AD) and other forms of dementia and cognitive dysfunction. Early brain changes associated with AD and other forms of cognitive dysfunction, such as white matter lesion (WML) burden, hypoperfusion and metabolic mismatch have vascular risk factors (hypertension, diabetes, aging and smoking). Such structural and functional brain changes are often considered secondary to intracranial cerebral small vessel disease. In contrast, our preliminary data indicate that extra-cranial carotid artery disease (ECAD) contributes to brain pathology and its treatment with carotid endarterectomy (CEA) (to surgically remove the plaque) decreases accumulation of WMLs and neurofibrillary tangles, increases structural connectivity, and most importantly, improves cognition. ECAD primarily signifies atherosclerosis of the carotid bifurcation, where plaque accumulation is uniquely prevalent compared to other cerebrovascular locations. Carotid arteries play a major role in brain physiology because they bring the majority of blood and nutrients to the brain. We hypothesize that mechanisms of ECAD contribution to Alzheimer’s disease and cognitive dysfunction are likely multifactorial and include embolic phenomena, decreased blood flow, and endothelial activation/inflammation. Interplay between these modifiable factors and non-modifiable risks (ie, age, sex and ApoE status) likely contribute to neurodegeneration that can lead to cognitive dysfunction. Our Aims 1 and 2 use cross-sectional studies to evaluate potential mechanisms of ECAD contribution to AD-related brain structure and function changes. Subject evaluation includes neurocognitive testing and quantification of MRI-defined structural parameters, WML accumulation, Alzheimer’s disease blood-based biomarkers, and systemic, cerebral and carotid markers of inflammation. Aim 3 employs a prospective, controlled cohort study evaluating the treatment of ECAD with CEA to determine which patients show improved cognitive function (responders) and what factors are drivers of this response. This project will define quantifiable measures of brain structural changes leading to neurodegeneration and cognitive dysfunction in subjects with ECAD. This should further build the impetus for clinical trials that change management of patients with ECAD. In addition, our study offers the exciting opportunity to reveal novel insights of early Alzheimer’s disease risk and specific mechanisms of vascular contributions. Understanding the unique contribution of ECAD to AD/cognitive dysfunction risk is particularly compelling because effective treatments exist for ECAD yet are not currently offered for the treatment/prevention of cognitive dysfunction.