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

基本信息

批准号：
7943096
负责人：
IRA T. LOTT
金额：
$ 55.89万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943096
关键词：
Adult Age Alzheimer&apos s Disease Alzheimer&apos 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 treatment 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 Research Personnel Risk Seizures Senile Plaques Severities Signaling Molecule Transforming Growth Factor beta 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

项目摘要

DESCRIPTION (Provided by Applicant): The objective of this application 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's disease. Individuals with Down syndrome have an increased incidence of Alzheimer's disease over age 40 years. Once dementia has begun, treatments appear to have little efficacy. 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. Specific Aim 2 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. The investigators predict that amyloid uptake will increase in those individuals with Down syndrome who go on to develop cognitive decline. Specific Aim 3 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, the investigators will focus on critical region mutations in mitochondrial DNA, with the hypothesis that their number will increase in association with cognitive decline. Additionally, they shall examine two key chemical components of Alzheimer's plaques and tangles (beta-amyloid and hyperphosporylated tau) in the cerebrospinal fluid. It is predicted 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's 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's disease in the general population. The investigators 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. Finally, Specific Aim 4 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. It is predicted that this model will form one basis for considering early intervention to prevent dementia in Down syndrome. This application 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. PROJECT NARRATIVE: This application is relevant to public health in predicting factors associated with cognitive decline and Alzheimer's disease in adults with Down syndrome. By developing a predictive model for cognitive decline, a rationale is established for early intervention to prevent or treat dementia. This project is relevant to individuals with Down syndrome and those at risk for Alzheimer's disease in the general population.

描述（由申请人提供）：本申请的目的是预测唐氏综合症成年人的认知能力下降，并最终提供一个早期干预的平台，以防止与阿尔茨海默氏病相关的痴呆症。患有唐氏综合症的个体在40岁以上的阿尔茨海默氏病发病率增加。痴呆症开始后，治疗似乎几乎没有疗效。这项研究将评估成像和生物标志物分析是否可以预测痴呆症发作之前唐氏综合症成年人的认知能力下降。认知能力下降将使用基于线人的电池和直接措施进行评估，这些措施表现出对与唐氏综合症发育衰老和痴呆症相关的变化的敏感性。具体目标1将确定定量EEG成像是否可以预测认知能力下降。当患有唐氏综合症的成年人癫痫发作时，认知能力下降可能会急剧下降。该目的旨在确定反映癫痫和脑电图混乱的神经生理标志物作为认知能力下降的预测指标。特定的目标2将通过正电子发射断层扫描作为痴呆的预测指标来评估淀粉样蛋白的摄取是否增加了大脑。患有唐氏综合症的个体在21染色体上具有淀粉样蛋白前体蛋白基因的一份。研究人员预测，淀粉样蛋白的摄取将增加唐氏综合症的患者，而唐氏综合症的那些继续发展认知能力下降的人。具体目标3将检查几种可能预测DS认知能力下降的生物标志物。基于涉及唐氏综合症的慢性氧化应激的证据，研究者将重点关注线粒体DNA中的关键区域突变，并假设其数量随认知能力下降而增加。此外，他们应检查脑脊液中阿尔茨海默氏菌的斑块和缠结的两个关键化学成分（β-淀粉样蛋白和phosporpory的tau）。据预测，脑脊液中的phosporyporytau水平增加和β-淀粉样蛋白水平较低的水平将预示认知能力下降，正如普通人群中阿尔茨海默氏病的患者所证明的那样。该目标还将检查脑脊液和血浆水平的炎症因子，这些因素已显示出普通人群中阿尔茨海默氏病改变。研究人员预测，导致唐氏综合症认知下降的病理过程将触发细胞因子，趋化因子和脊髓液和血浆生长因子变化的特征标志。最后，本研究的特定目的4试图开发一个预测模型，通过该模型，成像和生物标志物测量的变化将允许对认知能力下降的可能性进行综合评估。据预测，该模型将构成考虑早期干预以防止唐氏综合症痴呆症的一个基础。该应用与NICHD的使命一致，该使命将注意力引向预防常见发育障碍的人群中的疾病和残疾。项目叙述：这种应用与公共卫生有关，在预测唐氏综合症成年人认知能力下降和阿尔茨海默氏病有关的因素方面与公共卫生有关。通过开发认知能力下降的预测模型，可以建立一个理由以预防或治疗痴呆症。该项目与唐氏综合症的个体以及在普通人群中患阿尔茨海默氏病风险的人有关。