Aging of Frontal Structure and Function in Down Syndrome and Dementia

描述（由申请人提供）：唐氏综合症（DS）是人类智力残疾的主要原因，据估计，在美国有超过30万人患有这种遗传疾病。几乎所有的退行性痴呆患者在40岁时都有足够的神经病理学诊断为阿尔茨海默病（AD）。然而，痴呆症可能要到10年后才会发展，而且有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，以确定年龄和痴呆症相关的认知变化，特别是额叶功能。目标有四个方面。目的1将对一组患有退行性痴呆的成年人进行认知表征，并对这些个体进行为期5年的随访。目标2将使用磁共振成像技术每年对纵向随访的人进行白质完整性测量。目的3将检测每年从队列中抽取的血浆，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。目的4将研究来自DS成人的存档和新的尸检脑样本，以确定在AD发生之前和期间发生变化的分子途径。拟议研究的结果将有助于开发无创生物标志物，帮助DS的早期AD诊断和监测疾病进展。此外，与衰老、阿尔茨海默病神经病理学以及痴呆症相关的新型生物标志物也将为未来治疗性临床试验的设计提供结果，以治疗或预防退行性痴呆。

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.