Memory Advancement by Intranasal Insulin in Type 2 Diabetes (MemAID)

 描述（由申请人提供）：2型糖尿病（DM）加速大脑衰老，增加痴呆和阿尔茨海默病（AD）的风险。目前，还没有治疗DM相关的认知能力下降的方法。最近，鼻内胰岛素（INI）治疗已成为一种潜在的新的解决方案，将胰岛素安全地输送到大脑和治疗DM相关的认知障碍。我们的初步研究表明，单剂量40 IU的INI改善了2型糖尿病成人和健康对照组的特定认知领域和功能连接。先前的研究表明，短期INI治疗是安全的，可以改善非糖尿病认知障碍和AD患者的记忆力。这些研究提供了支持INI潜在有效性和安全性的概念验证;并为确定糖尿病人群中INI长期治疗的长期影响和安全性奠定了基础。我们提出以下目标：目标1：我们提出在200名患有2型DM的老年人和200名非糖尿病对照中进行随机、双盲、安慰剂对照研究，检查40 IU INI每日一次在24周期间是否改善：视觉空间注意力和记忆的特定领域，言语学习（主要结果）; B.与接受无菌盐水的DM组和非糖尿病组相比，在双重任务期间的步态速度（作为整体健康的预测因子）、日常生活功能和抑郁。非DM组将提供INI在正常衰老时发生的认知衰退和胰岛素抵抗的临床表型中的作用的参考。目标二：我们将确定一种表型，预测INI治疗的临床相关阳性反应，并确定INI对DM组与安慰剂组和非DM组学习和记忆影响的长期轨迹。将根据认知功能和步态与人口统计学、血糖控制、胰岛素抵抗、内皮功能和遗传（ApoE 4）指标之间的相关性确定临床相关预测因子。将在24周治疗期间和治疗后6个月评估认知、步态双重任务和功能表现的轨迹。MRI子研究将探索对灌注和静息状态功能连接的长期影响及其与认知结局的关系。目标3：确定鼻内胰岛素与安慰剂相比在血糖控制（空腹血糖、Hb 1Ac、低血糖发作）、生命体征和体重方面的长期安全性。这项研究将帮助我们确定长期INI治疗的安全性;最佳结局领域;以及未来大规模疗效研究中使用的最佳患者特征。临床表型和时间进程预测INI治疗的最佳反应将使其有可能靶向INI治疗，以最大限度地保护老年糖尿病患者的认知功能。

 DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (DM) accelerates brain aging and increases the risk for dementia and Alzheimer's disease (AD). Currently, there is no treatment for DM-related cognitive decline. Recently, intranasal insulin (INI) therapy has emerged as a potential new solution to deliver insulin safely to the brain and treat DM- related cognitive impairment. Our pilot study showed that a single INI dose of 40IU improved specific cognitive domains and functional connectivity in type 2 DM adults and healthy controls. Previous studies showed that short-term INI treatment is safe and may improve memory in non-diabetic people with cognitive impairment and AD. These studies provided proof-of-concept supporting the potential usefulness and safety of INI; and lay the ground work to determine the long-term effects and safety of prolonged treatment with INI in diabetic population. We propose the following Aims: Aim 1: We propose a randomized, double-blind, placebo-controlled study in 200 older adults with type 2 DM and 200 non-diabetic controls examining whether 40 IU INI once daily over a 24 week period improves: a. specific domains of visuospatial attention and memory, verbal learning (primary outcomes); b. gait speed during a dual task ( as a predictor of overall health), daily living functioning and depression as compared to the DM group receiving sterile saline and the non-diabetic groups. The non-DM groups will provide reference of INI effects in a clinical phenotype of cognitive decline and insulin resistance that occurs with normal aging. Aim 2: We will determine a phenotype predicting a clinically relevant positive response to INI therapy and identify long-term trajectories of INI effects on learning and memory in the DM group vs. the placebo and the non-DM groups. Clinically relevant predictors will be determined based on associations between cognitive function and gait and demographic, glycemic control, insulin resistance, endothelial function and genetic (ApoE4) measures. The trajectory of cognitive, gait dual task and functional performances will be assessed during the 24 weeks of therapy and at 6 months post-treatment. MRI substudy will explore long-term effects on perfusion and resting state functional connectivity and their relationships to cognitive outcomes. Aim 3: To determine the long-term safety of intranasal insulin vs. placebo with regard to glycemic control (fasting glucose, Hb1Ac, hypoglycemic episodes) and vital signs and body mass. This study will help us to determine the safety of prolonged INI treatment; the best outcome domains; and the best patient characteristics to be used in future large-scale efficacy studies. The clinical phenotype and time course predicting optimal response to INI therapy would make it possible to target INI treatment for maximal benefits for preserving cognitive function in older diabetic adults.