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.

项目总体描述：摘要 神经精神症状 (NPS) 是阿尔茨海默病 (AD) 和相关痴呆症的核心特征 与日常功能和生活质量的重大不利影响相关，并加速时间 在所有 NPS 中，抑郁症是轻度患者中最常见的症状。 随着疾病的进展，认知障碍和早期 AD 会出现烦躁、妄想和幻觉。 更常见，而冷漠是 AD 各个阶段中最持久和最常见的 NPS。 NPS 与严重精神疾病 (SMI) 具有一些共同的临床特征，例如精神分裂症、双相情感障碍 和重度抑郁症，但这些疾病是否具有相似的疾病尚不清楚。 AD 和其他痴呆症中不存在 NPS 的可靠治疗方法，因此需要更好地了解 AD 和其他神经精神疾病中 NPS 的分子机制和途径至关重要 下一步是确定可靠的生物标志物，从而开发出新的治疗方法。 该提案有两个总体目标：首先，我们将确定分子机制和。 AD 患者中与 NPS 存在相关的神经病理学变化 其次，我们将。 检查 AD 和 SMI 中与 NPS 相关的病理机制是否相同或不同。 具体来说，我们建议使用来自 1,264 个数据的表型组学和基因组学数据构建多尺度综合模型 来自单一脑库的尸检病例还包括详细的表型组学数据。 特征 NPS、临床诊断（AD 和其他神经退行性或神经精神特征）、严重程度 针对每个患者样本的认知能力下降和神经病理学，我们将应用创新技术。 减少与传统方法相关的成本和技术偏差并捕获基因的方法 单细胞水平的表达特征和表观遗传调控元件。 将应用于神经病理学变化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（例如基因表达和增强子序列的变化）， 预测 AD 和其他神经精神特征中的各种 NPS；我们将这些综合模型称为基因型 我们期望这些模型将使我们能够分配基因型和分子。 在单细胞水平上对 AD 内的特定 NPS 和其他神经精神特征进行标记，这是前所未有的 此外，我们将测试基因型-标记-表型模型的转化潜力。 使用独立的大规模生物库数据集来预测 AD-NPS，其中基因型和电子健康 成功完成拟议的研究将通过生成立即产生效用。 NPS 诊断和预后的潜在生物标志物，并为患者分层提供预测模型 从长远来看，我们的模型将帮助我们制定治疗策略和蓝图。 治疗 AD 中 NPS 的干预措施。