Plasma Amylin Impact on Cognitive Function and Brain Morphology in the Framingham Heart Study

胰淀素是一种肠-脑轴激素，其容易穿过血脑屏障（BBB）并介导 包括调节葡萄糖代谢、舒张脑血管结构和调节 炎症，所有这些都可能对阿尔茨海默病（AD）有益。最近的研究表明 轻度认知障碍（遗忘型MCI）和AD患者血浆中胰淀素浓度较低 比认知能力正常的老年人要高。在横断面分析中，较高浓度的血浆 胰淀素与更好的认知功能有关，特别是在记忆和执行领域。使用AD 在小鼠模型中，我们最近的研究表明，腹膜内注射胰淀素（i. p.）可以改善学习能力， 和记忆力以及降低脑中AD病理学指标。尽管这些研究表明， 外源性给予胰淀素型肽可能对AD有益，胰淀素也可在AD中形成淀粉样蛋白， 2型糖尿病的胰腺和AD脑的血管系统中可能导致恶化的 认知.因此，研究基线之间的纵向关系是非常重要和关键的 血浆胰淀素浓度与衰老过程中认知功能下降的关系。来自Framingham心脏 研究后代和Omni第1代队列，我们建议使用从1995年至2005年收集的血浆样本。 1998年与15年后认知和大脑结构的事件变化有关。我们能飞那么高 血浆胰淀素水平对衰老过程中的认知衰退和脑萎缩具有保护作用。我们有五 具体目的包括：1）研究血浆胰淀素在FHS社区人群中的分布; 2） 确定基线血浆胰淀素和认知变化之间的关系，包括事件性轻度 认知障碍和痴呆; 3）检查血浆胰淀素与 脑形态学; 4）通过ApoE 4等位基因、糖尿病和其他血管疾病的存在对这些分析进行分层; 5）研究胰淀素、胰淀素、脂质、其他肠-脑轴肽与疾病的关系， FHS炎症。普兰林肽是一种胰淀素类似物，是FDA批准的用于糖尿病的药物， 在临床使用中具有良好的安全性。我们是否应该发现高水平的血浆胰淀素对 AD发病率，我们的研究将为普兰林肽的大型2期或3期试验提供额外的理由， 确定胰淀素型肽是否可以预防和治疗AD。我们预计，这项研究可能有助于打开一个 新的和非传统的途径治疗AD。

Amylin is a gut-brain axis hormone, which readily crosses the blood brain barrier (BBB) and mediates activities including regulating glucose metabolism, relaxing cerebrovascular structure and modulating inflammation, all of which could be beneficial for Alzheimer’s disease (AD). Recent studies have shown that mild cognitive impairment (amnestic MCI) and AD patients have a lower concentration of amylin in plasma than the elderly who had normal cognition. In cross-sectional analyses, higher concentrations of plasma amylin are related to better cognitive function, especially in memory and executive domains. Using AD mouse models, our recent study demonstrates that intraperitoneal injection (i.p) of amylin improves learning and memory as well as reduces indices of AD pathology in the brain. Although these studies suggest that exogenous administration of amylin type peptides may be beneficial for AD, amylin can also form amyloid in the pancreas of type 2 diabetes and in the cerebrovasculature of AD brain that may lead to worsened cognition. Thus, it is important and critical to study the longitudinal relationship between the baseline concentration of plasma amylin and cognitive decline during aging process. From the Framingham Heart Study Offspring and Omni Generation 1 cohorts, we propose using plasma samples collected from 1995- 1998 to relate to incident change in cognition and brain structure up to 15 years later. We posit that high levels of plasma amylin are protective for cognitive decline and brain atrophy in aging process. We have five specific aims including 1) studying the distribution of plasma amylin in FHS community based population; 2) determining the relationship between baseline plasma amylin and cognitive changes, including incident mild cognitive impairment and dementia; 3) examining the association between plasma amylin and changes in brain morphology; 4) stratifying these analyses by the presence of ApoE4 allele, diabetes and other vascular diseases and 5) studying the relationship between amylin, A, lipids, other gut-brain axis peptides and inflammation in FHS. Pramlintide is an amylin analog and an FDA approved drug for diabetes with a favorable safety profile in clinical use. Should we find that high levels of plasma amylin are protective for the incidence of AD, our study will provide additional rationale for a large phase 2 or 3 trial with pramlintide to determine if amylin type peptides can prevent and treat AD. We anticipate that this study may help open a new and unconventional avenue for the therapeutic of AD.