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

唐氏综合症中的衰老和痴呆：连通性、炎症和脑血管的影响

• 批准号: 9212643
• 负责人: Elizabeth Head
• 金额: $ 49.64万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212643
• 关键词: Adult; Age; Age-Years; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Antigen-Antibody Complex; Attenuated; Autopsy; Behavior; Biological Markers; Blood; Brain; Case Series; Cerebrovascular Disorders; Chromosomes, Human, Pair 21; Classification; Clinical Trials; Cognition; Cognitive; Cognitive aging; Data; Dementia; Dependency; Development; Diagnosis; Diffuse; Down Syndrome; Employee Strikes; Encephalitis; Event; Future; Genes; Goals; Hereditary Disease; Human; Image; Impaired cognition; Individual; Inflammation; Inflammatory; Intellectual functioning disability; Intervention Studies; Link; Liquid substance; Longitudinal cohort; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Molecular; Molecular Target; Nerve Degeneration; Neurobiology; Neurofibrillary Tangles; Outcome; Parietal Lobe; Pathology; Pathway interactions; Pattern; Phenotype; Plasma; Play; Predisposition; Proteins; Quality of life; RNA; Recovery; Recruitment Activity; Reporting; Research; Research Design; Role; Senile Plaques; Signal Transduction; Spin Labels; Syndrome; Testing; United States; United States National Institutes of Health; Variant; abeta accumulation; abeta deposition; age related; aging brain; brain tissue; cerebrovascular; clinical imaging; cognitive function; cohort; functional decline; imaging modality; improved; middle age; neurobiological mechanism; neuroinflammation; neuropathology; novel; prevent; public health relevance; virtual; white matter

 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.

 描述（由适用提供）：唐氏综合症（DS）是人类智力残疾的主要原因，据估计，美国有30万人患有这种遗传疾病。实际上，所有DS个体都有足够的神经病理学来诊断40年的AD。但是，直到十年后，痴呆症可能不会发展，并且有些人在认知上保持完整。在这种竞争性更新中，我们建议继续遵循（并扩大）与DS的老年人组成的队列以及招募年轻人，以确立白质（WM）完整性损失，脑血管功能障碍（CVF）和神经炎症的作用。 AIM 1将继续在认知上表征与DS的成年人队列，并跟随个人5年，并招募一个年轻的病理学，这是AD AD病理学的年轻队列。使用扩散张量成像的磁共振成像（MRI）将用于跟踪WM完整性中的损耗。 AIM 2将使用MRI方法来检测易感加权成像，流体衰减的反转恢复和动脉自旋标记的脑血管功能障碍。 AIM 3将使用磁共振光谱和血液生物标志物来检测神经炎症是年龄，AD神经病理学和认知下降的函数。 AIM 4将测量蛋白质和RNA，以反映蛋白质和RNA的变化，以确定WM完整性，CVF中损失的神经生物学机制以及DS尸检病例大脑中神经炎症的变化。我们将能够确定可以实施干预研究的目标（AIM 4），以促进健康的大脑衰老，并导致认知（AIM 1），WM结构完整性（AIM 1）和CVF改进（AIM 2），并减少神经炎症（AIM 2）（AIM 3）在未来的临床试验中。确定最早的迹象 痴呆症和认知下降中个体变异的指标为实施DS的适当预防方法提供了机会，以减慢或停止AD神经病理的发展，并显着改善容易受到神经变性的DS个人的生活质量。