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

据估计，65岁以上的美国人口将从2014年的4600万增加到2019年的8800万 2050年，这一增长与阿尔茨海默病(AD)和其他疾病患病率的急剧上升同步 晚年认知综合症。到目前为止，还没有有效的治疗方法来延缓或逆转晚年的认知 拒绝。因此，通过改变风险因素进行预防是一项基本的战略。新陈代谢 功能障碍，通常最终导致临床诊断为2型糖尿病(T2 DM)或T2 DM前期， 其中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 可修改的，尚不清楚如何以最佳方式预防代谢的不利和潜在的长期影响 大脑功能障碍。导致这种不确定性的知识鸿沟是对 与神经元损伤相关的外周和中枢机制之间复杂的双向关系 有代谢功能障碍。不良的健康行为(如饮食不良和体力活动不足) 不良外周改变(如胰岛素抵抗、慢性高血糖)以及不良脑部改变 (例如，葡萄糖代谢不足、淀粉样蛋白堆积和脑血管功能障碍)。脑部变化 最终导致不良认知变化，进而可能促进不良健康行为。一直以来 Long认识到，早期生活因素可能会产生持久的后果，但目前尚不清楚血糖状态是否 儿童和青春期是几十年后认知变化的重要触发因素，以及是否如此 认知变化是由与AD相关的神经生物学底物推动的，如淀粉样蛋白。博加卢萨心脏研究 (BHS)是唯一正在进行的关于混血儿的终生研究(35%非裔美国人/65%白人；13%T2 DM，35% T2 DM前)的美国人群，从早期开始对代谢状态进行详细的、前瞻性的评估 从童年到中年，以及中年两个时间点的认知表现数据(平均年龄45岁 在1,298名男性和女性中)。该项目将使用神经成像和认知测试来探索长期的 与高正常早期生活平均禁食相关的术语认知结果(在600名BHS参与者中) 血糖(MFPG)以及与AD相关的神经生物学底物对这些结果的影响(250 BHS参与者还将接受3T脑MRI和PET)。这项研究的结果可能会影响空腹血糖 青少年指南以及是否应该开始降血糖治疗以避免长期不良反应 大脑的结果。该项目还将评估与AD相关的分子靶点是否可以被修改为阻止 生命早期高正常mFPG对脑的影响。

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.