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: 10020206
• 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/10020206
• 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; Prognostic Marker; 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; 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) 及其前驱阶段造成的医疗、社会和经济负担 病理学、轻度认知障碍（MCI）、退伍军人的地位刺激了确定治疗方法的努力 最近的证据表明，除了 AD 的血管异常之外， 内皮源性一氧化氮 (NO) 的缺乏可能会导致 AD-的产生和积累 相关的神经毒素，例如β淀粉样蛋白（Aβ），我们有能力克服这些挑战。 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 这些因素在 AD 中确实减弱了，因此，本研究的首要目的是确定内皮细胞是否具有影响。 通过测量静脉注射引起的脑血流量变化，功能与 AD 严重程度相关。 输注一氧化氮合酶 (NOS) 抑制剂 NG-单甲基-L-精氨酸 (L-NMMA) 直接评估脑功能 AD、MCI 患者以及认知正常年龄和性别匹配的对照患者中的 NO 生物利用度我们也进行了研究。 评估以确定更简单、非侵入性的外周内皮功能建议是否良好 本研究的第二个目的是确定内皮细胞的作用。 通过纵向评估和比较 AD 进展中的功能和 NO 生物利用度的变化 18 个月内内皮功能（大脑和外周）对认知功能变化的影响 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，以确定脑血管疾病是否 内皮功能和一氧化氮生物利用度是限制这种使人衰弱的疾病的可行治疗目标。