Understanding the molecular mechanisms that contribute to neuropsychiatric symptoms in Alzheimer Disease

了解导致阿尔茨海默病神经精神症状的分子机制

• 批准号: 10439255
• 负责人: STEVEN M FINKBEINER
• 金额: $ 44.14万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439255
• 关键词: Adverse effects; Agitation; Alzheimer' s Disease; Alzheimer' s disease related dementia; Autopsy; Biological Markers; Bipolar Disorder; Brain; Caregiver Burden; Cells; Clinical; Clinical Trials; Data; Data Set; Delusions; Dementia; Diagnosis; Disease; Electronic Health Record; Epigenetic Process; Gene Expression; Gene Expression Profile; Genetic Enhancer Element; Genetic Markers; Genotype; Goals; Hallucinations; Human; Impaired cognition; Institutionalization; Intervention; Lead; Major Depressive Disorder; Mental Depression; Methods; Modeling; Molecular; Nerve Degeneration; Pathology; Pathway interactions; Patients; Persons; Prognosis; Public Health; Quality of life; Regulatory Element; Research; Resolution; Sampling; Schizophrenia; Severities; Symptoms; Testing; Therapeutic; Time; biobank; brain tissue; care giving burden; cell type; clinical diagnosis; cost; daily functioning; deep learning; functional genomics; genomic data; high dimensionality; innovation; learning strategy; mild cognitive impairment; molecular marker; neuropathology; neuropsychiatric symptom; neuropsychiatry; novel; novel therapeutics; patient stratification; phenomics; phenotypic biomarker; potential biomarker; predictive modeling; severe mental illness; trait; translational potential

GENERAL PROJECT DESCRIPTION: ABSTRACT Neuropsychiatric symptoms (NPS) are core features of Alzheimer’s disease (AD) and related dementias that are associated with major adverse effects on daily function and quality of life, and accelerate time to institutionalization. Of all the NPS, depression is the most frequently observed symptom in people with mild cognitive impairment and early AD. As the disease progresses, agitation, delusions and hallucinations become more common, whereas apathy is the most persistent and frequent NPS throughout all the stages of AD. AD- NPS share some clinical features with serious mental illnesses (SMIs), such as schizophrenia, bipolar disorder and major depressive disorder, but whether these conditions share similar aethiopathies is unclear. Given that reliable treatments for NPS in the context of AD and other dementias do not exist, a better understanding of the molecular mechanisms and pathways underlying NPS in AD and other neuropsychiatric illnesses is a critical next step to identify reliable biomarkers that could lead to novel therapeutics. There are two overarching goals of this proposal. First, we will identify the molecular mechanisms and neuropathological changes that are associated with the presence of NPS in patients with AD. Second, we will examine if the mechanisms of pathology associated with NPS are shared or distinct among AD and SMIs. More specifically, we propose to build multi-scale integrative models using phenomics and genomics data from 1,264 autopsy cases derived from a single brain bank. The bank includes detailed phenomics data such as well characterized NPS, clinical diagnosis (AD and other neurodegenerative or neuropsychiatric traits), severity of cognitive decline and neuropathology for each patient sample. From each case, we will apply innovative approaches that reduce the cost and technical biases associated with conventional methods, and capture gene expression signatures and epigenetic regulatory elements at the single-cell level. Novel deep-learning methods will be applied for the multi-scale integration of neuropathologic changes with genetic markers and functional genomic changes (such as changes in gene expression and enhancer sequences) within specific cell types, to predict various NPS in AD and other neuropsychiatric traits; we refer to these integrative models as genotype- marker-phenotype models. We expect that these models will enable us to assign genotypes and molecular markers to specific NPS within AD and other neuropsychiatric traits at the single-cell level, an unprecedented level of resolution. In addition, we will test the translational potential of the genotype-marker-phenotype models to predict AD-NPS using independent large-scale biobank datasets, in which genotypes and electronic health records are available. Successful completion of the proposed studies will have immediate utility by generating potential biomarkers for NPS diagnosis and prognosis and by providing predictive models for patient stratification in clinical trials. In the longer term, our models will help us create a blueprint for therapeutic strategies and interventions to treat NPS in AD.

项目概述：摘要 神经精神症状(NPS)是阿尔茨海默病(AD)和相关痴呆的核心特征 与日常功能和生活质量的主要不良影响有关，并加速时间 制度化。在所有的NPS中，抑郁是轻度患者最常见的症状 认知障碍和早期阿尔茨海默病。随着疾病的发展，躁动、妄想和幻觉变得 更常见，而冷漠是AD所有阶段中最持久和最常见的NPS。广告- NPS与严重精神疾病(SMI)有一些共同的临床特征，如精神分裂症、双相情感障碍 和严重的抑郁障碍，但这些情况是否有相似的先天疾病尚不清楚。考虑到 在AD和其他痴呆的背景下，对NPS的可靠治疗不存在，更好地理解 阿尔茨海默病和其他神经精神疾病NPS的分子机制和通路是关键 下一步是确定可能导致新疗法的可靠生物标记物。 这项提议有两个首要目标。首先，我们将确定分子机制和 AD患者与NPS相关的神经病理改变。第二，我们将 检查与NPS相关的病理机制在AD和SMI中是否相同或不同。更多 具体地说，我们建议使用来自1,264个数据的表现学和基因组学数据来构建多尺度综合模型 尸检案例来自单一的脑库。该银行还包括详细的表型组学数据，如 NPS的特点、临床诊断(AD和其他神经退行性或神经精神病学特征)、严重程度 每个患者样本的认知功能减退和神经病理学。从每个案例中，我们将应用创新 降低与传统方法相关的成本和技术偏差的方法，并捕获基因 在单细胞水平上的表达特征和表观遗传调控元件。新的深度学习方法 将应用于神经病理改变与遗传标记和功能的多尺度整合 特定细胞类型内的基因组变化(如基因表达和增强子序列的变化)， 预测阿尔茨海默病和其他神经精神症状的各种NPS；我们将这些综合模型称为基因型- 标记-表型模型。我们希望这些模型将使我们能够确定基因类型和分子 在单细胞水平上，AD内特定NPS和其他神经精神特征的标志物，前所未有的 分辨率级别。此外，我们还将测试基因-标记-表型模型的翻译潜力 使用独立的大规模生物库数据集预测AD-NPS，其中基因型和电子健康 有记录可用。成功完成拟议研究将产生立竿见影的效果 NPS诊断和预后的潜在生物标志物以及为患者分层提供预测模型 在临床试验中。从长远来看，我们的模型将帮助我们为治疗策略和 AD患者NPS的干预治疗。