Early life glycemic status and Alzheimer's disease neuroimaging markers in middle age: the Bogalusa Heart Study

美国65岁以上的人口估计将从2014年的4600万增长到2015年的8800万。 2050年，这种增长导致阿尔茨海默病（AD）和其他疾病的患病率急剧增加。 晚年认知综合征到目前为止，还没有有效的治疗方法来阻止或逆转晚年的认知能力。 下降因此，通过改变危险因素进行预防是一项基本战略。代谢 通常在2型糖尿病（T2 DM）或前T2 DM的临床诊断中达到高潮的功能障碍， 这是一个非常普遍的可改变的风险因素。然而，虽然代谢功能障碍本身是 虽然可以改变，但目前尚不清楚如何最佳地预防代谢产物的不良和潜在的长期影响。 大脑功能障碍造成这种不确定性的知识差距是对 神经元损伤相关的外周和中枢机制之间复杂的双向关系 代谢紊乱不良健康行为（例如，不良饮食和体力活动不足） 不利的外周变化（例如，胰岛素抵抗、慢性高血糖症）以及不利的脑部变化 (e.g.,葡萄糖代谢减退、淀粉样蛋白积聚和脑血管功能障碍）。大脑变化 最终导致不利的认知变化，反过来又可能促进不利的健康行为。已经 长期以来，人们认识到早期生活因素可能会产生持久的后果，但尚不清楚血糖状态是否 是几十年后认知变化的重要触发因素， 认知变化是由AD相关的神经生物学底物如淀粉样蛋白驱动的。博加卢萨心脏研究 (BHS)是唯一一项正在进行的双胞胎（35%非洲裔美国人/65%白色人; 13% T2 DM，35% T2 DM前）美国人群，从早期开始详细、前瞻性收集代谢状态评估 童年到中年，以及中年两个时间点的认知表现数据（平均年龄45岁 1，298名男性和女性。该项目将使用神经成像和认知测试来探索长期- 与高正常早期生活平均值相关的长期认知结果（在600名BHS参与者中） 血浆葡萄糖（mFPG），以及这些结果的AD相关神经生物学底物（250例患者的子集） BHS参与者还将接受3 T脑部MRI和PET）。本研究的结果可能会影响FPG 青少年指南以及是否应开始血糖治疗以避免长期不良反应 脑的结果。该项目还将评估AD相关的分子靶点是否可能被修饰以阻断 早期生活对大脑的影响高正常mFPG。

The U.S. population greater than 65 years of age is estimated to grow from 46 million in 2014 to 88 million in 2050, and that growth has paralleled dramatic increases in prevalence of Alzheimer's disease (AD) and other late life cognitive syndromes. To date, there is no effective treatment to stall or reverse late life cognitive decline. Therefore, prevention, through modification of risk factors, is an essential strategy. Metabolic dysfunction, which often culminates in a clinical diagnosis of type 2 diabetes mellitus (T2DM) or pre-T2DM, is one such modifiable risk factor that is highly prevalent. However, while metabolic dysfunction itself is modifiable, it is not clear how to optimally prevent adverse and potentially long-lasting effects of metabolic dysfunction on the brain. The knowledge gap driving this uncertainty is incomplete understanding of the complex, bi-directional relationships between peripheral and central mechanisms of neuronal injury associated with metabolic dysfunction. Adverse health behaviors (e.g., poor diet and inadequate physical activity) induce adverse peripheral changes (e.g., insulin resistance, chronic hyperglycemia) as well as adverse brain changes (e.g., glucose hypometabolism, amyloid accumulation, and cerebrovascular dysfunction). Brain changes culminate in adverse cognitive changes that in turn may promote the adverse health behaviors. It has been long recognized that early life factors can have lasting consequences, yet it is unknown whether glycemic status in childhood and adolescence is an important trigger of cognitive changes decades later, and whether such cognitive changes are driven by AD-related neurobiological substrates like amyloid. The Bogalusa Heart Study (BHS) is the only on-going, life-course study of a biracial (35% African American/65% white; 13% T2DM, 35% pre-T2DM) U.S. population, with detailed, prospectively-collected assessments of metabolic status from early childhood through mid-life, and cognitive performance data at two time points in midlife (average age of 45 years) among 1,298 men and women. This project will use neuroimaging and cognitive testing to explore long- term cognitive outcomes (among 600 BHS participants) associated with high-normal early-life mean Fasting Plasma Glucose (mFPG), as well as AD-related neurobiological substrates for these outcomes (a subset of 250 BHS participants will also undergo 3T brain MRI and PET). The results of this study could impact FPG guidelines among adolescents and whether glycemic treatment should to be initiated avoid long-term adverse brain outcomes. The project will also assess whether AD-related molecular targets may be modified to block the impact on the brain of early life high-normal mFPG.