Midcareer Investigator Award in Amylin, Cognition, and Alzheimer's Disease

 描述(由申请人提供)：这份K24申请的目标是为候选人提供受保护的时间来进行以患者为导向的研究，并扩大她目前的指导计划。虽然这位候选人在神经退行性疾病方面建立了临床研究的记录，但她也有推动学员职业生涯和研究的记录。最近的研究表明，轻度认知障碍(遗忘性MCI)和阿尔茨海默病(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。胰淀素是一种肠-脑轴激素，它很容易穿过血脑屏障，调节葡萄糖代谢、松弛脑血管结构和调节炎症等活动，这些都可能对AD有利。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)检查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、Aβ、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): The goal of this K24 application is to provide protected time for the candidate to conduct patient-oriented research and to expand her current program of mentoring. While the candidate has established a record of clinical research in neurodegeneration, she also has track record of advancing her mentees' careers and research as well. Recent studies have shown that mild cognitive impairment (amnestic MCI) and Alzheimer's disease (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. 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 AD. 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 f 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.