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

基本信息

批准号：
10835430
负责人：
STEVEN M FINKBEINER
金额：
$ 42.12万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
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/10835430
关键词：
Acceleration Administrative Supplement Adverse effects Agitation Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Autopsy BRAIN initiative Biological Markers Bipolar Disorder Brain Caregiver Burden Cell Nucleus Cells Clinical Clinical Trials Data Data Set Delusions Dementia Development Diagnosis Disease Disease Progression Electronic Health Record Gene Expression Genomics Genotype Goals Hallucinations Human Impaired cognition Institutionalization Intervention Major Depressive Disorder Mental Depression Modeling Molecular Molecular Profiling Nerve Degeneration Outcome Pathology Pathway interactions Persons Prefrontal Cortex Prognosis Quality of life Resolution Schizophrenia Severities Symptoms Taxonomy Testing Therapeutic Time biobank brain tissue caregiving cell type clinical diagnosis cohort daily functioning gene regulatory network genetic risk factor genomic data high dimensionality mild cognitive impairment molecular marker neuropathology neuropsychiatric symptom neuropsychiatry novel therapeutics parent grant parent project patient stratification phenomics phenotypic biomarker potential biomarker predictive modeling severe mental illness therapeutically effective trait translational potential

Acceleration Administrative Supplement Adverse effects Agitation Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Autopsy BRAIN initiative Biological Markers Bipolar Disorder Brain Caregiver Burden Cell Nucleus Cells Clinical Clinical Trials Data Data Set Delusions Dementia Development Diagnosis Disease Disease Progression Electronic Health Record Gene Expression Genomics Genotype Goals Hallucinations Human Impaired cognition Institutionalization Intervention Major Depressive Disorder Mental Depression Modeling Molecular Molecular Profiling Nerve Degeneration Outcome Pathology Pathway interactions Persons Prefrontal Cortex Prognosis Quality of life Resolution Schizophrenia Severities Symptoms Taxonomy Testing Therapeutic Time biobank brain tissue caregiving cell type clinical diagnosis cohort daily functioning gene regulatory network genetic risk factor genomic data high dimensionality mild cognitive impairment molecular marker neuropathology neuropsychiatric symptom neuropsychiatry novel therapeutics parent grant parent project patient stratification phenomics phenotypic biomarker potential biomarker predictive modeling severe mental illness therapeutically effective trait translational potential

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项目摘要

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. The overarching goals of the parent grant are to: (1) identify the molecular mechanisms and neuropathological changes that are associated with the presence of NPS in patients with AD; and (2) examine if the mechanisms of pathology associated with NPS are shared or distinct among AD and SMIs. More specifically, we are currently building gene regulatory networks to integrate phenomics and genomics data (genotypes, single nucleus profiles from dorsolateral prefrontal cortex) from 1,500 autopsy cases. Detailed phenomics data such as well characterized NPS, clinical diagnosis (AD and other neurodegenerative or neuropsychiatric traits), severity of cognitive decline and neuropathology are being utilized. 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. This administrative supplement will further enhance these efforts by leveraging human brain single-cell data generated as part of large consortia, including BICAN, SEA-AD, psychENCODE, AMP-PD, and AMP-AD, to validate molecular mechanisms and pathways that are shared or distinct across AD and SMIs. 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.

项目摘要神经精神症状（NP）是阿尔茨海默氏病（AD）和相关痴呆的核心特征与对日常功能和生活质量的重大不利影响相关，并加速时间制度化。在所有NP中，抑郁症是中间患者中最常观察到的症状认知障碍和早期广告。随着疾病的发展，躁动，妄想和幻觉变得更常见的是，在AD的所有阶段，冷漠是最持久和常常的NP。广告- NP与严重的精神疾病（SMI）共享一些临床特征，例如精神分裂症，躁郁症和主要的抑郁症，但是这些疾病是否具有类似的嗜thi症尚不清楚。鉴于在AD和其他痴呆症的背景下，对NP的可靠治疗不存在，更好地理解 AD和其他神经精神疾病中NP的分子机制和途径是关键下一步确定可靠的生物标志物，可能导致新的治疗。父授予的总体目标是：（1）确定分子机制和神经病理学与AD患者中NP有关的变化；（2）检查机制是否与NP相关的病理学在AD和SMI中共享或独特。更具体地说，我们目前正在构建基因调节网络以整合现象学和基因组学数据（基因型，单核谱图从1,500例尸检病例中摘自承载前额叶皮层）。详细的现象学数据，例如 NP的特征，临床诊断（AD和其他神经退行性或神经精神特征），严重程度正在利用认知能力下降和神经病理学。我们希望这些模型将使我们能够分配在单细胞处的AD和其他神经精神特征内特定NP的基因型和分子标记级别，空前的分辨率水平。此外，我们将测试基因型的翻译潜力使用独立的大型生物库预测AD-NP的标记 - 表型模型，其中提供基因型和电子健康记录。这种行政补充将通过利用人脑单细胞数据进一步增强这些努力作为大型财团的一部分，包括Bican，Sea-AD，Psychencode，AMP-PD和AMP-AD 验证在AD和SMIS中共享或不同的分子机制和途径。成功的拟议的研究的完成将立即通过为NP产生潜在的生物标志物。诊断和预后，并通过在临床试验中提供患者分层的预测模型。更长的时间术语，我们的模型将帮助我们创建一种用于治疗AD中NP的治疗策略和干预措施的蓝图。