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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：
10450771
负责人：
STEVEN M FINKBEINER
金额：
$ 183.32万
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/10450771
关键词：
Adverse effects Agitation Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Autopsy Biological Biological Assay Biological Markers Biological Models Bipolar Disorder Brain Caregiver Burden Cell Nucleus Cells Clinical Clinical Trials Data Data Set Delusions Dementia Development Diagnosis Disease Electronic Health Record Elements Enhancers Epigenetic Process Epitopes Factor Analysis Gene Expression Gene Expression Profile Genes Genetic Enhancer Element Genetic Markers Genetic Variation Genomics Genotype Goals Hallucinations Human Impaired cognition Institutionalization Intervention Lead Link Machine Learning Major Depressive Disorder Measurement Medicine Mental Depression Methods Modeling Molecular Nerve Degeneration Nuclear Outcome Output Pathology Pathway interactions Patients Pattern Persons Phenotype Prefrontal Cortex Prognosis Quality of life Regulatory Element Research Resolution Sampling Schizophrenia Severities Slide Structure Symptoms Testing Therapeutic Time Tissues Variant Weight associated symptom biobank brain tissue care giving burden cell type clinical application clinical diagnosis clinical predictors cohort cost daily functioning deep learning epigenome epigenomics functional genomics genetic risk factor genetic variant genomic data high dimensionality indexing innovation interest learning strategy mild cognitive impairment molecular marker neuropathology neuropsychiatric symptom neuropsychiatry novel novel therapeutics patient stratification phenomics phenotypic biomarker potential biomarker predictive modeling prognostic model severe mental illness therapeutically effective trait transcriptome transcriptomics translational potential

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. 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.

项目总结