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

颅外颈动脉粥样硬化导致认知障碍和阿尔茨海默病风险

• 批准号: 10300801
• 负责人: Craig C Weinkauf
• 金额: $ 84.5万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10300801
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Anisotropy; Apolipoprotein E; Atherosclerosis; Blood; Blood Vessels; Blood flow; Brain; Brain Pathology; Brain imaging; Carotid Arteries; Carotid Artery Diseases; Carotid Atherosclerotic Disease; Carotid Endarterectomy; Carotid Stenosis; Cerebral small vessel disease; Cerebrum; Clinical Trials; Cognition; Cohort Studies; Cross-Sectional Studies; Data; Data Analyses; Dementia; Diabetes Mellitus; Disease; Education; Endothelium; Evaluation; Event; Goals; Hippocampus (Brain); Hypertension; Impaired cognition; Inflammation; Intervention; Knowledge; Lead; Lesion; Location; Longitudinal prospective study; Magnetic Resonance Imaging; Measures; Metabolic; Nerve Degeneration; Neurofibrillary Tangles; Nutrient; Observational Study; Operative Surgical Procedures; Outcome; Participant; Pathologic; Pathway interactions; Patient Recruitments; Patients; Physiological; Physiology; Play; Population; Prevention; Process; Relative Risks; Research Design; Risk; Risk Reduction; Role; Secondary to; Smoking; Stenosis; Structure; Testing; Ultrasonography; United States; Vascular Dementia; Vascular Diseases; Work; base; blood-based biomarker; brain health; brain volume; cardiovascular risk factor; cerebral hypoperfusion; cerebrovascular; cognitive function; cohort; defined contribution; dementia risk; effective therapy; follow-up; hypoperfusion; imaging scientist; improved; inflammatory marker; insight; multidisciplinary; neurocognitive test; novel; patient population; predicting response; prevent; prospective; recruit; response; risk stratification; sex; systemic inflammatory response; targeted treatment; vascular contributions; vascular risk factor; white matter

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.

项目摘要/摘要 越来越需要了解与血管贡献相关的机制和治疗选择 阿尔茨海默病(AD)和其他形式的痴呆症和认知功能障碍。早期脑部变化 与AD和其他形式的认知功能障碍有关，如白质损伤(WML)负担， 低灌注率和代谢不匹配有血管危险因素(高血压、糖尿病、衰老和吸烟)。 这种结构和功能的改变通常被认为是继发于脑内小血管。 疾病。相反，我们的初步数据表明，颅外颈动脉疾病(ECAD)对 颈动脉内膜剥脱术(CEA)(手术清除斑块)对脑病理的影响 减少WML和神经原纤维缠结的积累，增加结构连通性，并且大多数 重要的是，它可以改善认知。 ECAD主要表示颈动脉分叉处的动脉粥样硬化，斑块的聚集是唯一的。 与其他脑血管部位相比，发病率较高。颈动脉在脑生理学中起着重要作用 因为它们将大部分血液和营养带到大脑。我们假设ECAD的机制 导致阿尔茨海默病和认知功能障碍的因素可能是多因素的，其中包括血栓 现象，血流减少，内皮细胞活化/炎症。这些可修改组件之间的相互作用 因素和不可改变的风险(例如，年龄、性别和载脂蛋白E状态)可能会导致神经变性，这可能 会导致认知功能障碍。我们的目标1和2使用横断面研究来评估潜在的机制 ECAD在AD相关脑结构和功能改变中的作用。学科评价包括 神经认知测试和MRI定义的结构参数、WML积聚、阿尔茨海默病的量化 疾病的血液生物标志物，以及全身、脑和颈动脉炎症的标志物。AIM 3雇佣了一名 评价CEA治疗ECAD的前瞻性对照队列研究确定哪些患者 显示改善的认知功能(响应者)，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和 ECAD受试者的认知功能障碍。这应该会进一步推动临床试验的变革 ECAD患者的管理。此外，我们的研究提供了揭示新奇见解的令人兴奋的机会 早期阿尔茨海默病风险和血管作用的具体机制。了解独一无二的 ECAD对AD/认知功能障碍风险的贡献特别引人注目，因为有效 ECAD的治疗方法已经存在，但目前还没有提供用于治疗/预防认知障碍的方法 功能障碍。