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Developing a clinical and research framework for evaluating inflammation pathway dysregulation in Alzheimer's disease

开发评估阿尔茨海默病炎症途径失调的临床和研究框架

基本信息

批准号：
10323668
负责人：
Gurkan Bebek
金额：
$ 16.1万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323668
关键词：
Accounting Acute Address Age Age-Years Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer’s disease biomarker Animal Model Autopsy Behavioral Bioinformatics Biological Factors Biological Markers Brain CCL2 gene Cause of Death Cerebrospinal Fluid Clinical Clinical Research Clinical dementia rating scale Cognitive Data Data Analyses Data Set Databases Dementia Diagnostic Disease Disease Progression Drug Targeting Education Foundations Future Gene Targeting Genes Genetic Genetic Polymorphism Genetic Transcription Goals Health Heterogeneity Human Impaired cognition Inflammation Inflammatory Inflammatory Response Intervention Knowledge Longitudinal cohort Magnetic Resonance Imaging Medicine Modeling Molecular Mutation Nerve Degeneration Neuraxis Neurofibrillary Tangles Outcome Pathologic Pathway interactions Patient Care Patients Persons Play Positron-Emission Tomography Predictive Factor Public Health Regulator Genes Reporting Research Research Personnel Risk Role Senile Plaques Sum TREM2 gene Techniques Testing Therapeutic Up-Regulation Work apolipoprotein E-4 base brain tissue clinical biomarkers clinical care clinically relevant cognitive change cohort cytokine design differential expression gene network gene regulatory network genome wide association study genome-wide improved individual variation inflammatory marker insight interest mild cognitive impairment neuroimaging neuroinflammation neuropathology novel novel therapeutic intervention peripheral blood pre-clinical precision medicine predictive modeling prevent response sex systemic inflammatory response therapeutic target tissue resource transcriptome sequencing translational study

项目摘要

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia worldwide. In the US, it is the fifth leading cause of death in people over 65 years of age. Delineating factors that predict rate of future cognitive decline and dementia are important but are yet to be thoroughly understood. Knowledge of disease progression related biological factors will be critical in designing novel therapeutic strategies to mitigate their deleterious effects and thereby prevent the associated cognitive and behavioral decline. The research at the foundation of this R03 is a clinical translational study that uses bioinformatics and large data analysis techniques to characterize the transcriptional and clinical context of dysregulated inflammatory pathway changes in the brain and periphery that impact longitudinal cognitive decline in different stage of AD. This information will be integrated with prior data on known biomarkers of AD to develop a clinically useful model to focus better targeted patient care. Our earlier work among clinical AD patients at the Mild cognitive impairment stage the disease studies suggest that a clinically meaningful degree of rapid cognitive decline was best predicted by baseline levels of an inflammatory marker, CCL2. In this work we hope to extend this initial insight by characterizing in depth the genetic drivers behind the inflammatory deregulation in clinical AD in the periphery and the central nervous system. We will confirm and validate these changes with genome wide (RNA-seq) expression changes and against data from other large national data (Alzheimer's Disease Neuroimaging Initiative, Accelerating Medicines Partnership-AD and Harvard Brain Tissue Resource Center). These results will be integrated with our knowledge of temporal changes in established AD biomarkers in different clinical stages, to develop a clinically useful framework. The scientific insights and clinical models from this research will help target novel inflammation based therapeutic targets in the most effective stage of AD among clinical patients after taking into account individual variability for deleterious inflammatory responses. This is a much needed step for future precision medicine interventions against neuroinflammation in AD to prevent disease progression.

项目总结/文摘