Biomarkers of Alzheimer's Disease in Adults with Down Syndrome

患有唐氏综合症的成人中阿尔茨海默病的生物标志物

基本信息

批准号：
9754500
负责人：
IRA T. LOTT
金额：
$ 33.84万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754500
关键词：
Academic Medical Centers Activities of Daily Living Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Archives Atrophic Behavioral Bioinformatics Biological Biological Assay Biological Markers Blood Blood Banks Blood specimen Brain Candidate Disease Gene Cerebrospinal Fluid Cerebrum Classification Clinical Clinical Research Clinical Trials Cognition Cognitive Communities Core Facility DNA Data Data Set Dementia Deposition Deterioration Disease Progression Down Syndrome Ethnic group Evaluation Future General Population Genes Genetic Polymorphism Genomics Health Health Status Image Individual Inflammatory Laboratories Lipids Machine Learning Magnetic Resonance Imaging Measurement Measures Methods Modality Modeling Neurocognitive Neurodegenerative Disorders Onset of illness Outcome Participant Pathology Pathway interactions Patients Peptides Pilot Projects Plasma Population Positron Positron-Emission Tomography Proteins Proteomics Protocols documentation Research Research Infrastructure Research Personnel Resources Risk Running Sampling Scientist Screening procedure Serum System Testing Therapeutic Intervention Therapeutic Trials Tissues Work amyloid pathology base biobank biomarker identification blood-based biomarker clinical Diagnosis clinical predictors clinical risk cohort demented early detection biomarkers experience forest genetic variant genomic data high risk human model imaging biomarker imaging study improved insight interdisciplinary approach member metabolomics mild cognitive impairment mouse model multidisciplinary multiple omics neuroimaging normal aging novel novel therapeutics pre-clinical rate of change screening tau Proteins tomography tool uptake validation studies white matter

项目摘要

Abstract By age 40 years, individuals with Down syndrome (DS) show the neuropathological changes of Alzheimer’s disease (AD) and have a high risk for dementia, but little is known about the biomarkers that may predict clinical onset or reflect disease progression. The ABC-DS study focuses on a longitudinal and multidisciplinary determination of key biomarkers that are likely to define this progression, including levels and rates of change in blood based biomarkers such as b-amyloid peptides, protein and lipid profiles, and measures of amyloid and tau concentration in cerebrospinal fluid, neuroimaging-based changes and genetic polymorphisms. Using a neurocognitive battery that we have developed and tested, systematic profiles of longitudinal stability and of decline will allow us to define dementia status, including Mild Cognitive Impairment in DS (MCI-DS), and characterize progression in clinical status. Previously generated protein, inflammatory and lipid signatures will be examined, as well as amyloid and tau profiles in cerebrospinal fluid (CSF). Imaging biomarkers will include structural MRI components and PET studies of brain amyloid uptake and tau protein. Analysis of MRI imaging biomarkers will include longitudinal measures of atrophy, white matter abnormalities and intrinsic network connectivity paradigms. Amyloid positron tomography will delineate regional and whole brain uptake of amyloid and tau deposition. Polymorphisms in candidate genes for AD and related biomarkers will be studied as potential modifiers of risk and their relation to beta amyloid, proteomic, lipidomic and imaging biomarkers examined. Relationships among demographic, clinical, blood based and CSF biomarkers, imaging measures, and genetic variants will be examined to develop the most valid indicators of preclinical and early stages of AD. The addition of non-targeted proteomics (n=7,000 proteins) will provide the single largest and richest dataset to date for the study of AD in adults with DS The identification of a blood-based profile that can be highly accurate in identifying people at risk and in screening out people who have a low likelihood of having cerebral amyloid and/or tau would be of tremendous value to novel clinical trials an approach has tremendous potential for revolutionizing the current system. Importantly, the data and the biological samples will be archived and banked to establish a resource to be shared with other scientists. Collectively, our investigators have a combined clinical and research experience involving over 1500 patients (30% demented), over 850 banked blood samples, 500 DNA samples, and 50 imaging studies. Further, team investigators have previous experience with all methods that will be included in this new project. This proposal brings together a group of co-investigator with established expertise in studies of DS and makes available a combined cohort of 400 participants.

抽象的到 40 岁时，唐氏综合症 (DS) 患者会表现出阿尔茨海默病的神经病理学变化疾病（AD）并且具有很高的痴呆风险，但对于可以预测的生物标志物知之甚少 ABC-DS 研究侧重于纵向和多学科的临床发病或反映疾病进展。确定可能定义这一进展的关键生物标志物，包括变化水平和速率血液中的生物标志物，如 b-淀粉样肽、蛋白质和脂质谱，以及淀粉样蛋白和淀粉样蛋白的测量脑脊液中 tau 浓度、基于神经影像的变化和遗传多态性。我们开发并测试了神经认知电池，纵向稳定性和下降将使我们能够定义痴呆症状态，包括 DS 轻度认知障碍 (MCI-DS)，以及表征先前产生的蛋白质、炎症和脂质特征的进展。以及脑脊液 (CSF) 中的淀粉样蛋白和 tau 蛋白谱进行检查。大脑淀粉样蛋白摄取和 tau 蛋白的结构 MRI 成分和 PET 研究 MRI 成像分析。生物标志物将包括萎缩、白质异常和内在网络的纵向测量淀粉样蛋白正电子断层扫描将描绘淀粉样蛋白的区域和全脑摄取。 AD 候选基因和相关生物标志物的多态性将被研究为风险的潜在修饰因素及其与 β 淀粉样蛋白、蛋白质组、脂质组和成像生物标志物的关系检查了人口统计学、临床、血液和脑脊液生物标志物、影像学测量之间的关系。将检查遗传变异，以制定 AD 临床前和早期阶段的最有效指标。添加非靶向蛋白质组学（n=7,000 个蛋白质）将提供最大、最丰富的单一数据集迄今为止，对患有 DS 的成人进行 AD 研究确定了基于血液的特征，该特征可以高度准确识别高危人群并筛选出患有脑病可能性较低的人淀粉样蛋白和/或 tau 蛋白对于新型临床试验具有巨大价值，一种具有巨大潜力的方法重要的是，数据和生物样本将被存档和保存。总的来说，我们的研究人员拥有一个与其他科学家共享的资源。涉及超过 1500 名患者（30% 患有痴呆症）的综合临床和研究经验，超过 850 名患者此外，团队研究人员之前还进行了血液样本、500 个 DNA 样本和 50 个成像研究。该提案汇集了一组对将包含在这个新项目中的所有方法的经验。联合研究者在 DS 研究方面拥有丰富的专业知识，并提供了 400 人的联合队列参与者。