Aging and Dementia in Down Syndrome: Connectivity, Inflammation, and Cerebrovascular Contributions

 描述（由申请人提供）：唐氏综合征（DS）是人类智力残疾的主要原因，据估计，在美国有超过30万人患有这种遗传性疾病。几乎所有的DS个体在40岁时都有足够的神经病理学诊断AD。然而，痴呆症可能要到十年后才会发展，有些人的认知能力仍然完好无损。在这次竞争性更新中，我们建议继续跟踪（并扩大）我们的老年DS患者队列，并招募年轻个体，以确定白色完整性丧失、脑血管功能障碍（CVF）和神经炎症对认知功能下降的作用。目标1将继续对DS成人队列进行认知表征，并对个体进行为期5年的随访，同时招募AD前病变的年轻队列。采用弥散张量成像的磁共振成像（MRI）将用于跟踪WM完整性的损失。目的2将磁敏感加权成像、液体衰减反转恢复和动脉自旋标记技术应用于脑血管功能障碍的诊断。目标3将使用磁共振波谱和血液生物标志物来检测神经炎症作为年龄，AD神经病理学和认知能力下降的函数。目的4将测量蛋白质和RNA以反映蛋白质和RNA的变化，以确定DS尸检病例脑中WM完整性丧失、CVF和神经炎症变化的神经生物学机制。我们将能够确定干预研究的目标（目标4），这些目标可以促进健康的大脑老化，并在未来的临床试验中导致认知（目标1），WM结构完整性（目标1）和CVF改善（目标2）以及减少神经炎症（目标3）。识别最早的迹象 痴呆症和认知衰退的个体差异指标提供了实施DS适当预防方法的机会，以减缓或停止AD神经病理学的发展，并显着改善易受神经变性影响的DS个体的生活质量。

 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 AD in their 40th year. However, dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses, cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline. Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity. Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging, fluid attenuated inversion recovery and arterial spin labeling. Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age, AD neuropathology and declines in cognition. Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity, CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1), WM structural integrity (Aim 1), and CVF improvements (Aim 2), and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signs of dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.