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: 10629361
• 负责人: Craig C Weinkauf
• 金额: $ 116.1万
• 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/10629361
• 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; Carotid Arteries; Carotid Artery Diseases; Carotid Atherosclerotic Disease; Carotid Endarterectomy; Carotid Stenosis; Cephalic; 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; Hypertension; Impaired cognition; Inflammation; Intervention; Knowledge; Lesion; Location; Magnetic Resonance Imaging; Measures; Metabolic; Nerve Degeneration; Neurofibrillary Tangles; Nutrient; Observational Study; Operative Surgical Procedures; Outcome; Participant; Pathologic; Pathway interactions; Patient Recruitments; Patient Selection; Patients; Physiological; Physiology; Play; Population; Prevention; Process; Relative Risks; Research Design; Risk; Risk Reduction; Role; Secondary to; Smoking; Stenosis; Structure; Testing; United States; Vascular Dementia; Vascular Diseases; Work; 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; longitudinal, prospective study; multidisciplinary; neurocognitive test; novel; patient population; predicting response; prevent; prospective; recruit; response; risk stratification; sex; systemic inflammatory response; targeted treatment; ultrasound; 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方案 阿尔茨海默氏病（AD）和其他形式的痴呆和认知功能障碍。早期大脑变化 与AD和其他形式的认知功能障碍有关，例如白质病变（WML）Burnen， 灌注不足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）。 这种结构性和功能性大脑变化通常被认为是颅内脑小血管的继发 疾病。相反，我们的初步数据表明颅外颈动脉疾病（ECAD）有助于 脑病理学及其用颈动脉内膜切除术（CEA）治疗（以手术去除斑块） 降低WML和神经纤维缠结的积累，增加结构连接性，大多数 重要的是，改善认知。 ECAD主要表示颈动脉分叉的动脉粥样硬化，其中斑块积累是独特的 与其他脑血管相比，普遍存在。颈动脉在脑生理中起主要作用 因为它们将大多数血液和营养物质带入大脑。我们假设ECAD的机制 对阿尔茨海默氏病和认知功能障碍的贡献可能是多因素的，包括栓塞 现象，血流减少和内皮激活/炎症。这些修改之间的相互作用 因素和不可修改的风险（即，年龄，性别和APOE状态）可能有助于神经变性 导致认知功能障碍。我们的目标1和2使用横截面研究来评估 ECAD对与广告相关的大脑结构和功能变化的贡献。主题评估包括 MRI定义的结构参数，WML积累，阿尔茨海默氏症的神经认知测试和定量 疾病基于血液的生物标志物以及炎症的全身性，脑和颈动脉标记。瞄准3员工 预期的，受控的队列研究评估ECAD用CEA治疗以确定哪些患者 显示改善的认知功能（响应者）以及该反应的驱动因素是什么因素。 该项目将定义可量化的大脑结构变化的量度，导致神经变性和 ECAD受试者的认知功能障碍。这应该进一步建立变化的临床试验的动力 ECAD患者的管理。此外，我们的研究提供了激动人心的机会来揭示新的见解 阿尔茨海默氏病早期的风险和血管贡献的特定机制。了解独特 ECAD对AD/认知功能障碍风险的贡献特别令人信服，因为有效 ECAD的治疗方法目前尚未用于治疗/预防认知 功能障碍。