Predicting Cognitive Decline in Adults with Down Syndrome

预测患有唐氏综合症的成年人的认知能力下降

• 批准号: 8520361
• 负责人: IRA T. LOTT
• 金额: $ 41.51万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520361
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Biological Markers; Brain; Brain imaging; Cerebrospinal Fluid; Characteristics; Chemicals; Child; Chromosomes, Human, Pair 21; Chronic; Clinical; Cognitive deficits; Comorbidity; Corpus striatum structure; Data; Dementia; Deposition; Development; Down Syndrome; Early Intervention; Electroencephalogram; Epilepsy; Feedback; Financial cost; Gene Mutation; General Population; Genes; Growth Factor; Image; Image Analysis; Impaired cognition; Incidence; Individual; Inflammatory; Language; Longevity; Measures; Memory impairment; Mission; Mitochondrial DNA; Modeling; Morbidity - disease rate; Mutation; National Institute of Child Health and Human Development; Neurofibrillary Tangles; Neurologic; Oxidative Stress; Pathologic Processes; Patients; Pattern; Peripheral; Pittsburgh Compound-B; Plasma; Population; Positron-Emission Tomography; Public Health; Research; Risk; Seizures; Senile Plaques; Severities; Signaling Molecule; Transforming Growth Factor beta; abstracting; age related; base; cerebral atrophy; chemokine; cytokine; developmental disease; directed attention; disability; disorder prevention; experience; granulocyte; informant; mind control; monocyte; mortality; neurophysiology; predictive modeling; presenilin; prevent; tau Proteins; tau-1; uptake

Project Summary/Abstract The objective of this proposal is to predict cognitive decline in adults with Down syndrome and to ultimately provide a platform for early intervention to prevent the dementia associated with Alzheimer disease. Individuals with Down syndrome have an increased incidence of Alzheimer disease over age 40 years. Once dementia has begun, treatments appear to have little efficacy. The specific aims of this study will assess whether imaging and biomarker analysis will predict cognitive decline in adults with Down syndrome prior to the onset of dementia. Cognitive decline will be assessed using a battery of informant based and direct measures which demonstrate sensitivity to changes associated with developmental aging and dementia in Down syndrome. Specific aim 1 will determine whether quantitative EEG imaging will predict cognitive decline. When adults with Down syndrome develop seizures, the cognitive decline may become precipitous. This aim seeks to identify neurophysiological markers reflecting epilepsy and EEG disorganization as predictors of cognitive decline. The 2nd specific aim will assess whether amyloid uptake is increased in brain by positron emission tomography as a predictor of dementia. Individuals with Down syndrome have triplication of the amyloid precursor protein gene on chromosome 21. We predict that amyloid uptake will increase in those individuals with Down syndrome who go on to develop cognitive decline. The 3rd specific will examine several biomarkers that have a high likelihood of predicting cognitive decline in DS. Based upon the evidence implicating chronic oxidative stress in Down syndrome, we will focus on critical region mutations in mitochondrial DNA with the hypothesis that their number will increase in association with cognitive decline. Additionally, we shall examine 2 key chemical components of Alzheimer plaques and tangles (beta-amyloid and hyperphosporylated tau) in the cerebrospinal fluid. We predict that increased levels of hyperphosporylated tau and lower levels of beta-amyloid in cerebrospinal fluid will herald cognitive decline as has been demonstrated in patients with Alzheimer disease in the general population. This aim will also examine cerebrospinal fluid and plasma levels for inflammatory factors that have been shown to be altered in Alzheimer disease in the general population. We predict that pathological processes leading to cognitive decline in Down syndrome will trigger a characteristic signature of changes in cytokines, chemokines and growth factors in spinal fluid and plasma. The final aim of this study seeks to develop a predictive model by which the changes in imaging and biomarker measures will allow a composite assessment of the likelihood of cognitive decline. We predict that this model will form one basis for considering early intervention to prevent dementia in Down syndrome. This proposal is consistent with the mission of NICHD in directing attention towards the prevention of disease and disability in a population with a common developmental disorder.

项目概要/摘要 该提案的目的是预测患有唐氏综合症的成年人的认知能力下降，并最终 提供一个早期干预平台，以预防与阿尔茨海默病相关的痴呆症。个人 患有唐氏综合症的人在 40 岁以上患阿尔茨海默病的发病率会增加。一旦痴呆 已经开始，治疗似乎收效甚微。本研究的具体目的将评估是否 成像和生物标志物分析将预测唐氏综合症成人在发病前的认知能力下降 痴呆症。将使用一系列基于信息的直接测量来评估认知能力下降 表现出对与唐氏综合症发育衰老和痴呆相关的变化的敏感性。 具体目标 1 将确定定量脑电图成像是否可以预测认知能力下降。当成年人与 唐氏综合症会出现癫痫发作，认知能力可能会急剧下降。这一目标旨在确定 反映癫痫和脑电图紊乱的神经生理学标志物是认知能力下降的预测因素。这 第二个具体目标是通过正电子发射断层扫描评估大脑中淀粉样蛋白的摄取是否增加 痴呆症的预测因子。患有唐氏综合症的个体具有淀粉样前体蛋白基因的三倍体 位于 21 号染色体上。我们预测唐氏综合症患者的淀粉样蛋白摄取量将会增加 继续发展认知能力下降。第三个具体项目将检查几种可能性很高的生物标志物 预测 DS 认知能力下降。基于唐氏慢性氧化应激的证据 综合征，我们将重点关注线粒体 DNA 的关键区域突变，假设它们的数量 会随着认知能力下降而增加。此外，我们还将检查 2 个关键化学成分 脑脊液中的阿尔茨海默病斑块和缠结（β-淀粉样蛋白和过度磷酸化的 tau）。我们 预测脑脊液中高磷酸化 tau 蛋白水平升高，β-淀粉样蛋白水平降低 预示着认知能力下降，正如阿尔茨海默病患者所证明的那样 人口。该目标还将检查脑脊液和血浆中炎症因子的水平，这些炎症因子具有 已被证明在普通人群的阿尔茨海默病中发生了改变。我们预测病理性 导致唐氏综合症认知能力下降的过程将引发特征性变化 脊髓液和血浆中的细胞因子、趋化因子和生长因子。本研究的最终目的是 开发一个预测模型，通过该模型，成像和生物标志物测量的变化将允许综合 评估认知能力下降的可能性。我们预测该模型将构成考虑的基础 早期干预以预防唐氏综合症痴呆。该提案与我们的使命是一致的 NICHD 将注意力集中在具有共同疾病和残疾的人群中 发育障碍。