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

 描述(申请人提供)：胰淀素是一种肠-脑轴激素，很容易穿过血脑屏障(BBB)，调节葡萄糖代谢、放松脑血管结构和调节炎症等活动，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(遗忘性MCI)和AD患者的血浆胰淀素浓度低于认知正常的老年人。在横断面分析中，较高的血浆胰淀素浓度与更好的认知功能有关，特别是在记忆和执行领域。利用AD小鼠模型，我们最近的研究表明，腹腔注射胰淀素(I.P)可以改善学习和记忆，并降低大脑中AD的病理指标。尽管这些研究表明外源性给予胰淀素类肽可能对AD有益，但胰淀素也可以在2型糖尿病患者的胰腺和AD大脑的脑血管系统中形成淀粉样蛋白，从而可能导致认知恶化。因此，研究衰老过程中血浆胰淀素基线浓度与认知功能减退之间的纵向关系具有重要意义。从弗雷明翰心脏研究的后代和OMNI第一代队列中，我们建议使用1995-1998年间收集的血浆样本来研究15年后认知和大脑结构的意外变化。我们认为，高水平的血浆胰淀素对衰老过程中的认知衰退和脑萎缩具有保护作用。我们有五个具体目标，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与认知变化，包括偶发的轻度认知障碍和痴呆的关系；3)检测血浆胰淀素与脑形态变化的关系；4)根据ApoE4等位基因的存在对这些分析进行分层，糖尿病和其他血管疾病；5)研究胰淀素、A、血脂、其他肠-脑轴肽与FHS炎症的关系。普拉林肽是一种胰淀素类似物，是FDA批准的治疗糖尿病的药物，临床使用安全性良好。如果我们发现高水平的血浆胰淀素对AD的发生具有保护作用，我们的研究将为使用普拉林肽进行大型2期或3期试验提供额外的理论基础，以确定胰淀素类肽是否可以预防和治疗AD。我们预计，这项研究可能有助于为AD的治疗开辟一条新的非常规途径。

 DESCRIPTION (provided by applicant): 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.