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

项目总结 神经精神症状(NPS)是阿尔茨海默病(AD)及其相关疾病的核心特征 痴呆症与日常功能和生活质量的主要不良影响有关，并加速 到了制度化的时候了。在所有的NPS中，抑郁是最常见的症状 轻度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 变得更加普遍，而冷漠是在所有阶段中最持久和最频繁的NPS 广告。AD-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、躁郁症 精神障碍和严重抑郁障碍，但这些情况是否有类似的先天疾病尚不清楚。 鉴于阿尔茨海默病和其他痴呆症背景下的NPS不存在可靠的治疗方法，更好的方法是 阿尔茨海默病和其他神经精神疾病NPS潜在的分子机制和途径的理解 疾病是确定可靠的生物标记物的关键下一步，这些生物标记物可能导致新的治疗方法。 这项提议有两个首要目标。首先，我们将确定分子机制 以及与AD患者NPS存在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中是相同的还是不同的。 更具体地说，我们建议使用表现学和基因组学数据构建多尺度综合模型 来自单一脑库的1264例尸检。该银行包括详细的表型组学数据，如 特征明确的NPS、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提供预测模型 临床试验中的分层。从长远来看，我们的模型将帮助我们创建一幅治疗蓝图 AD患者NPS的治疗策略和干预措施。

PROJECT SUMMARY 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.