Effects of metabolic phenotype on functional connectivity in aging and Alzheimer’s Disease

摘要/摘要 阿尔茨海默病(AD)是导致痴呆症的最常见原因，影响着超过620万美国人和50 全球有一百万人。在认知症状出现前10到15年，AD病理学 开始出现在大脑中。而与AD相关的主要病理包括淀粉样β蛋白和 过度磷酸化的tau蛋白，AD的发病机制仍不清楚。阿尔茨海默病大脑的其他变化包括 大脑葡萄糖代谢紊乱。最近的流行病学研究强调了一种关联 阿尔茨海默病和全身性代谢损伤(如糖尿病)之间的关系。这表明了改变的主要作用 AD中的代谢，并有理由检查代谢风险如何有助于大脑健康和 痴呆症风险。脑结构和功能的生物标志物研究为早期发现提供了潜在的机会 为了提高我们对与疾病风险相关的因素的理解。功能连接，a 可以通过静息状态函数来测量两个大脑区域中相关神经活动的度量 磁共振成像(RsfMRI)。这种功能性神经成像方法已经成为一种潜在的 AD诊断和疾病监测的生物标志物。重要的是，新陈代谢风险以前 与功能连通性改变相关。然而，关于早期形式的代谢风险的数据，如 糖尿病前期，是缺乏的。此外，功能连通性研究通常受到样本量有限和 缺乏多样性。我们打算分析现有的rsfMRI数据，这些个人被招募到健康和 拉丁裔长老中的脑老化研究(HABLE)，一个约2,000人的不同队列。在我们的 第一个目标，我们将描述代谢风险的影响(糖尿病前期或2型糖尿病状态通过以下评估 血糖、诊断或用药)对认知健康个体的功能连通性的影响。AS 作为这一目标的一部分，我们还将研究APOE4的作用，APOE4是AD的一个最重要的遗传风险因素，与 与脑血管功能障碍有关。在我们的第二个目标中，我们将检查AD上的功能网络 诊断谱，并检查代谢风险在多大程度上调节这些网络的变化。我们会 然后评估心脏代谢风险评分与整体功能连接之间的关系 一群人。

Summary/Abstract Alzheimer’s Disease (AD), the most common cause of dementia, affects over 6.2 million Americans and 50 million individuals worldwide. Ten to fifteen years prior to the onset of cognitive symptoms, AD pathology begins to appear in the brain. While the primary pathology associated with AD include amyloid beta and hyperphosphorylated tau, the pathogenesis of AD remains elusive. Other changes in the AD brain include derangements in cerebral glucose metabolism. Recent epidemiological studies have highlighted an association between AD and systemic metabolic impairment (i.e. diabetes). This indicates a major role of altered metabolism in AD, and warrants examination of how metabolic risk may contribute to brain health and dementia risk. Biomarker studies of brain structure and function offer potential opportunities for early detection of AD, and for improving our understanding of factors relating to disease risk. Functional connectivity, a measure of correlated neural activity in two brain regions can be measured by resting-state functional magnetic resonance imaging (rsfMRI). This functional neuroimaging approach has emerged as a potential biomarker for AD diagnosis and disease monitoring. Importantly, metabolic risk has previously been associated with altered functional connectivity. However, data regarding early forms of metabolic risk, like prediabetes, is lacking. Additionally, functional connectivity studies often suffer from limited sample size and a lack of diversity. We intend to analyze the existing rsfMRI data of individuals recruited into the Health and Aging Brain Among Latino Elders (HABLE) Study, a diverse cohort of approximately 2,000 individuals. In our first aim, we will characterize the effect of metabolic risk (prediabetes or Type 2 Diabetes status assessed by blood glucose, diagnosis, or medication use) on functional connectivity in cognitively healthy individuals. As part of this aim, we will also examine the role of APOE4, a foremost genetic risk factor of AD that is closely related to cerebrovascular dysfunction. In our second aim, we will examine functional networks across the AD diagnostic spectrum, and examine to what degree metabolic risk mediates changes in these networks. We will then assess the relationship between cardiometabolic risk score and functional connectivity across the entire cohort.