A multi-omic approach to elucidate novel disease mechanisms and biomarkers for psychosis in Alzheimer’s disease

采用多组学方法阐明阿尔茨海默病精神病的新疾病机制和生物标志物

• 批准号: 9897065
• 负责人: Julia K Kofler
• 金额: $ 37.91万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897065
• 关键词: Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Automobile Driving; Autopsy; Biological Markers; Blood; Blood specimen; Brain; Clinical; Cognition; Collection; DNA Methylation; Data; Data Set; Delusions; Dementia; Development; Disease; Disease Progression; Early identification; Etiology; Gene Expression; Genetic Fingerprintings; Genetic Polymorphism; Genetic study; Genome; Genomics; Grant; Hallucinations; Hospitalization; Impaired cognition; Individual; Intervention; Licensing; Link; Methodology; Modeling; Molecular; Molecular Disease; Molecular Genetics; Multiomic Data; Network-based; Neurobiology; Patients; Peripheral; Pharmaceutical Preparations; Prefrontal Cortex; Process; Progressive Disease; Psychotic Disorders; Regulation; Research; Research Methodology; Risk; Sampling; Schizophrenia; Series; Single Nucleotide Polymorphism; Specificity; Stratification; Stroke; Symptoms; Syndrome; Testing; Tissue Sample; United States National Institutes of Health; Variant; Work; analytical method; atypical antipsychotic; base; biomarker development; cell type; cohort; effective therapy; epigenomics; genetic profiling; genome-wide; genomic profiles; methylomics; mild cognitive impairment; mortality; multiple omics; neuroimaging; neuropathology; neuropsychiatry; new therapeutic target; novel; psychotic symptoms; symptom treatment; transcriptomics

PROJECT SUMMARY Psychosis is an often debilitating syndrome occurring in 40-60% of people with Alzheimer's disease (AD). Psychosis in AD (AD+P) is associated with a more severe disease course, mortality, hospitalization, carer burden and faster decline in cognition and function. Atypical antipsychotics – first developed for schizophrenia - are widely used off license to treat these symptoms, with minimal benefits and considerable harm, including a 1.5- to 1.8-fold increase in mortality and a 3- fold increase in stroke. The development of safe and effective therapies for AD+P is an urgent priority, which has to start with a better understanding of disease mechanisms. There is abundant evidence from post-mortem, neuroimaging and genetic studies that AD-P is associated with a distinct profile of neurobiological changes but little is known about the molecular processes driving etiology. Moreover, one of the most robust clinical correlates of AD+P is a more rapid cognitive decline the trajectory of which appears to diverge before the onset of symptoms, suggests that stratification of individuals early in the disease by biomarkers that suggest the individual will develop psychosis could bring clinical benefits by identifying individuals at risk of AD+P and targeting interventions to them before the onset of symptoms. Thus, in this project we will test our overall hypothesis that AD+P is characterized by specific molecular changes in both the brain and blood that cut across multiple layers of genomic regulation. The main aim of this project is to identify novel disease mechanisms and biomarkers of AD+P, via the following specific aims; 1: Identify novel disease mechanisms implicated in AD+P; 2: Identify specific signatures of psychotic symptoms in blood samples of individuals with AD+P and evaluate their potential to predict whether individuals with MCI are more likely to develop AD; 3: Elucidate the extent to which psychotic symptoms in AD are mechanistically linked to schizophrenia The study brings together unique sample cohorts, cutting-edge methodologies and world-leading experts in genome regulation, clinical neuropsychiatry and AD neuropathology. This project builds on the state-of-the-art research methods utilized in our previously successful NIH R01 grants. The project will provide a major step forward in identifying 1) novel drug targets for AD+P, 2) better treatment of AD+P with existing medications and 3) novel peripheral biomarkers to predict which individuals with MCI will develop AD+P and are thus more likely to have a rapidly progressive disease course.

项目摘要 精神病是40-60％的阿尔茨海默氏病（AD）中经常发生的使人衰弱的综合征。 AD的精神病（AD+P）与更严重的疾病病程，死亡率，住院，护理人员烧伤有关 认知和功能的速度更快。非典型抗精神病药 - 首次用于精神分裂症 - 是 广泛使用的许可证来处理这些符号，受到最小的好处和巨大伤害，包括1.5-- 死亡率增加1.8倍，中风增加3倍。安全有效疗法的发展 对于AD+P是紧迫的优先事项，必须从更好地理解疾病机制。有 验尸，神经影像学和遗传研究的丰富证据表明，AD-P与独特的 神经生物学变化的特征，但对驱动病因的分子过程知之甚少。而且， AD+P最强大的临床相关性之一是认知较快下降的轨迹 要在症状发作之前发散，表明疾病早期的个体分层 表明个人会发展精神病的生物标志物可以通过识别来带来临床益处 在症状发作之前，患有AD+P的风险并针对干预措施。那，这是 项目我们将检验我们的总体假设，即AD+P的特征是两者的特定分子变化 跨基因组调节层切断的大脑和血液。该项目的主要目的是确定 通过以下特定目的，AD+P的新型疾病机制和生物标志物； 1：确定新型疾病 在AD+P中实施的机制； 2：确定血液样本中精神病症状的特定签名 患有AD+P的个体，并评估他们的潜力，以预测MCI的个体是否更有可能 开发广告； 3：阐明AD中的精神病症状在机械上与 精神分裂症 该研究汇集了独特的样本队列，尖端方法和世界领先的专家 基因组调节，临床神经精神病学和AD神经病理学。这个项目建立在最先进的基础上 在我们以前成功的NIH R01补助金中使用的研究方法。该项目将提供一个重大步骤 识别1）AD+P的新型药物靶标，2）用现有药物更好地治疗AD+P 3）新型的外围生物标志物可以预测哪些具有MCI的个体将发展为AD+P，因此更有可能 要有快速进行性疾病病程。