Aging of Frontal Structure and Function in Down Syndrome and Dementia

描述(申请人提供)：唐氏综合症(DS)是人类智力残疾的主要原因，据估计，美国有超过30万人患有这种遗传疾病。几乎所有的DS患者在他们40岁时都有足够的神经病理来诊断阿尔茨海默病(AD)。然而，痴呆症可能要到十年后才会发展，一些人的认知能力仍然完好无损。因此，研究人员试图在五年的时间里跟踪一组年龄在20-40岁之间的成年人，以确定与年龄和痴呆症相关的认知变化，特别是关注额叶功能。目标有四个方面。目标1将对一组患有DS的成年人进行认知特征描述，并对个人进行为期五年的跟踪调查。Aim 2将使用磁共振成像每年测量纵向跟踪的人的脑白质完整性。AIM 3将检测每年从队列中提取的血浆，并测量信号蛋白的变化，以确定AD发展的生物标志物，以及与认知相关的生物标志物。AIM 4将研究DS成人的存档和新的尸检大脑样本，以确定在AD发生之前和期间发生变化的分子途径。建议的研究结果将有助于非侵入性生物标志物的开发，这些生物标志物将有助于DS的早期AD诊断和监测疾病进展。此外，与衰老、AD神经病理以及痴呆症机械相关的新型生物标记物也将为未来治疗或预防DS痴呆的临床试验的设计提供结果。 项目简介：这项拟议的研究将确定检测患有唐氏综合症(DS)的成人阿尔茨海默病(AD)的新方法，方法是监测认知功能的变化，通过磁共振成像测量大脑变化，以及分析血浆中蛋白质的模式。同时，对大脑样本的尸检研究将帮助我们了解非侵入性认知、成像和血液测量如何反映DS患者AD的发展。如果早期发现疾病，治疗DS中的AD将更加有效，识别生物标志物将极大地促进治疗学的发展。

DESCRIPTION (Provided by Applicant): Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) in their 40th year. However, dementia may not develop until up to a decade later, and some people remain cognitively intact. Thus, the investigators seek to follow a group of adults ranging in age from 20-40 years over a five year period of time to identify age and dementia-associated changes in cognition, and in particular focus on frontal lobe function. The aims are four-fold. Aim 1 will cognitively characterize a cohort of adults with DS and follow individuals for a period of five years. Aim 2 will use magnetic resonance imaging to measure white matter integrity on an annual basis in longitudinally followed people. Aim 3 will assay plasma drawn annually from the cohort and measure signaling protein changes to identify biomarkers of AD development and that are also correlated with cognition. Aim 4 will study archived and new autopsy brain samples from DS adults to identify molecular pathways that change prior and during AD development. The outcomes of the proposed studies will contribute to the development of noninvasive biomarkers that will assist in early AD diagnosis in DS and monitor disease progression. Further, novel biomarkers that are mechanistically related to aging, AD neuropathology as well as dementia will also provide outcomes for the design of future therapeutic clinical trials to treat or prevent dementia in DS. PROJECT NARRATIVE: The proposed study will identify new ways in which to detect Alzheimer's disease (AD) in adults with Down syndrome (DS) by monitoring changes in cognitive function, measuring brain changes by magnetic resonance imaging, and profiling patterns of proteins in the plasma. In parallel, autopsy studies of brain samples will help us to understand how noninvasive cognitive, imaging, and blood measures reflect the development of AD in DS. Treatments for AD in DS will be more effective if the disease is detected early, and identifying biomarkers will greatly facilitate the development of therapeutics.