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

阿尔茨海默病(AD)及其前驱阶段的医疗、社会和经济负担 病理，轻度认知障碍(MCI)，放置在退伍军人身上刺激了寻找治疗方法的努力 目标来修改他们的进度。最近的证据表明，除了阿尔茨海默病的血管异常外， 内皮源性一氧化氮(NO)的缺乏可能有助于AD的产生和积聚。 相关的神经毒素，如淀粉样β蛋白(Aβ)。作为挑战，我们独一无二地准备克服， 阻碍了对脑血管内皮细胞功能的体内评估，并且没有生物利用度，目前尚不清楚 这些因素确实在AD中减弱了。因此，这项研究的第一个目的是确定内皮细胞 通过测量静脉注射引起的脑血流的变化，功能与AD的严重程度相关 一氧化氮合酶抑制剂L-精氨酸的直接脑保护作用 AD患者、MCI患者和认知正常的年龄和性别匹配的对照组中没有生物利用度。我们也 建议确定更简单、非侵入性的外周内皮功能评估是否良好 脑内皮细胞功能的替代物。这项研究的第二个目标将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的生物利用度的变化 内皮功能(脑和外周)与18个月认知功能变化的关系 在MCI患者中，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细胞在AD严重程度和进展中的作用，以确定脑组织 内皮功能和无生物利用度是限制这种衰弱疾病的可行治疗靶点。

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.