Vascular Endothelial Function: A Potential Therapeutic Target in Alzheimer's Disease

血管内皮功能：阿尔茨海默病的潜在治疗靶点

• 批准号: 10394118
• 负责人: Russell S. Richardson
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394118
• 关键词: Age; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Attenuated; Biological Availability; Blood flow; Caliber; Cerebrovascular Circulation; Cerebrum; Clinical; Cognitive; Core-Binding Factor; Disease; Disease Progression; Doppler Ultrasound; Economic Burden; Endothelium; Exhibits; Goals; Hyperemia; Impaired cognition; Intravenous infusion procedures; Leg; Link; Measurement; Measures; Mediating; Medical; Metabolic; Movement; Neurodegenerative Disorders; Neurotoxins; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthetase Inhibitor; Pathology; Patients; Peripheral; Play; Prevalence; Production; Protein Fragment; Rest; Role; Severities; Severity of illness; Time; Vascular Endothelium; Vasodilation; Veterans; amnestic mild cognitive impairment; atherogenesis; brachial artery; cerebrovascular; cognitive control; cognitive function; endothelial dysfunction; experience; fight against; in vivo; middle cerebral artery; mild cognitive impairment; neurotoxic; omega-N-Methylarginine; prognostic indicator; rate of change; sex; social; targeted treatment; therapeutic target; vascular abnormality; vascular endothelial dysfunction

The medical, social, and economic burdens that Alzheimer's disease (AD) and the prodromal stage of this pathology, mild cognitive impairment (MCI), place on Veterans has stimulated efforts to identify therapeutic targets to modify their progression. Recent evidence suggests that, in addition to vascular abnormalities in AD, a deficiency in endothelium-derived nitric oxide (NO) may contribute to the production and accumulation of AD- related neurotoxins such as amyloid beta (Aβ). As challenges, which we are uniquely poised to overcome, have deterred the in vivo assessment of cerebral endothelial function and NO bioavailability, it is unclear if these factors are, indeed, attenuated in AD. Therefore, the first aim of this study is to determine if endothelial function is related to AD severity by measuring the change in cerebral blood flow elicited by the intravenous infusion of the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) to directly assess cerebral NO bioavailability in patients with AD, MCI, and cognitively-normal age and sex matched controls. We also propose to determine if simpler, non-invasive assessments of peripheral endothelial function are good surrogates for cerebral endothelial function. The second aim of this study will determine the role of endothelial function and NO bioavailability in AD progression by longitudinally assessing and comparing the change in endothelial function (cerebral and peripheral) to the change in cognitive function over the course of 18 months in patients with MCI and age and sex matched controls. Thus, the overall goal of the proposed studies is to better understand the role of the vascular endothelium in AD severity and progression to determine if cerebral endothelial function and NO bioavailability are viable therapeutic targets to limit this debilitating disease.

阿尔茨海默病（AD）及其前驱期的医疗，社会和经济负担 病理学，轻度认知障碍（MCI），对退伍军人的地方刺激了努力，以确定治疗 目标是改变他们的进展。最近的证据表明，除了AD中的血管异常外， 内皮源性一氧化氮（NO）的缺乏可能有助于AD的产生和积累。 相关的神经毒素，如淀粉样蛋白β（Aβ）。作为挑战，我们有能力克服， 阻碍了脑内皮功能和NO生物利用度的体内评估，尚不清楚是否 这些因素确实在AD中减弱。因此，本研究的第一个目的是确定内皮细胞 功能与AD严重程度相关，通过测量由静脉内给药引起的脑血流量变化， NO合成酶（NOS）抑制剂NG-单甲基-L-精氨酸（L-NMMA）的输注，以直接评估大脑 AD、MCI患者和认知正常年龄和性别匹配对照组中NO的生物利用度。我们也 建议确定外周内皮功能的简单、非侵入性评估是否良好 脑内皮功能的替代物。本研究的第二个目的是确定内皮细胞的作用， 功能和NO生物利用度在AD进展中的纵向评估和比较， 内皮功能（大脑和外周）对认知功能变化的影响 MCI患者以及年龄和性别匹配的对照组。因此，拟议研究的总体目标是 更好地了解血管内皮在AD严重程度和进展中的作用，以确定脑血管内皮是否 内皮功能和NO生物利用度是限制这种使人衰弱的疾病的可行的治疗靶点。