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Common mechanistic biomarkers of vascular and neuro-degeneration

血管和神经变性的常见机制生物标志物

基本信息

批准号：
10567120
负责人：
YONGMEI LIU
金额：
$ 82.93万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10567120
关键词：
Acceleration Affect African American Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer’s disease biomarker Amyloid beta-42 Amyloid beta-Protein Atherosclerosis Autophagocytosis Biological Markers Blood Vessels Brain Brain imaging Carotid Arteries Cells Cerebrovascular Circulation Chinese Clinical Cognitive Communities Coupled DNA DNA methylation profiling Data Dementia Diagnosis Disease Elderly Epigenetic Process FOXO3A gene Genomics Glial Fibrillary Acidic Protein Goals Hippocampus Hispanic Human Impaired cognition Impairment In Vitro Intervention Light Link Longitudinal Studies Magnetic Resonance Imaging Measures Mediating Molecular Multi-Ethnic Study of Atherosclerosis Multiomic Data Mus Nerve Degeneration Neurocognitive Neurons Participant Pathogenesis Pathology Pathway interactions Permeability Plasma Positron-Emission Tomography Process SIRT1 gene Signal Transduction Structure Testing Thick Thinness Time Visit White Matter Hyperintensity adjudication arterial stiffness brain magnetic resonance imaging cardiometabolic risk cardiometabolism clinical imaging cognitive testing cohort dementia risk ethnic diversity experimental study gene network genome sequencing imaging biomarker improved in vivo insight longevity gene mRNA sequencing methylomics middle age mild cognitive impairment monocyte neurofilament predictive modeling proteostasis racial diversity screening tau Proteins tau-1 transcriptomics vascular cognitive impairment and dementia whole genome β-amyloid burden

项目摘要

Arterial stiffness, a vascular aging biomarker, has emerged as an important risk factor for dementia, and is being cross-sectionally linked to brain MRI-measured neurodegeneration and PET-measured brain Aβ and Tau burden, imaging biomarkers of Alzheimer’s disease (AD) and AD related dementias (ADRD). However, mechanisms by which arterial stiffness may contribute to cognitive impairment and dementia are incompletely understood. Recently, several plasma biomarkers including phosphorylated tau (p-tau) has emerged as promising surrogates for Aβ/Tau PET burden and neurodegeneration. The goal of this application is to characterize AD pathology/neurodegeneration connecting arterial stiffness to cognitive impairment using plasma biomarkers, and identify the diverse and overlapping mechanisms underlying vascular and neuro-degeneration associated with cognitive impairment through the following aims: A1. To quantify plasma biomarkers of AD/neurodegeneration, and determine effects of baseline and progression of arterial stiffness on changes of the plasma biomarkers. A2. To examine effects of monocyte genomic features (DNA methylomics and transcriptomics) on vascular aging. A3. To examine effects of monocyte genomic features on changes of the plasma biomarkers of AD/ neurodegeneration. A4. To test effects of SIRT1 on vascular and neuro-degeneration and AD pathogenesis using in vitro and in vivo AD models. The proposed longitudinal study adding plasma biomarkers of neurodegeneration to the racially and ethnically diverse MESA cohort with multi-omics data, carotid vascular and other cardiometabolic measures, brain imaging, cognitive testing, and clinical MCI/ADRD data across the mid- to late-life transition period, coupled with in vitro and in vivo experimental studies, has the potential to elucidate the contributions of arterial stiffness to cognitive impairment and identify molecular and cellular mechanisms that can explain the common co-occurrence of vascular and early AD/neurodegenerative pathologies and could serve as targets for disease-modifying interventions.

动脉僵硬度是血管老化的生物标志物，已成为动脉硬化的重要危险因素。痴呆症，并且与大脑MRI测量的神经变性和 PET测量的脑Aβ和Tau负荷，阿尔茨海默病（AD）的成像生物标志物， AD相关痴呆（ADRD）。然而，动脉僵硬可能导致认知障碍和痴呆症的关系还不完全清楚。近日，数台等离子包括磷酸化tau（p-tau）的生物标志物已经成为 Aβ/Tau PET负荷和神经变性。此应用程序的目标是表征AD 使用血浆将动脉僵硬与认知障碍联系起来的病理学/神经变性生物标志物，并确定血管和通过以下目的治疗与认知障碍相关的神经变性：A1.到定量AD/神经变性的血浆生物标志物，并确定基线和动脉硬化的进展对血浆生物标志物的变化。A2.检验…的影响单核细胞基因组特征（DNA甲基化组学和转录组学）对血管老化的影响。A3.到检查单核细胞基因组特征对AD/AD患者血浆生物标志物变化的影响。神经变性A4.为了测试SIRT 1对血管和神经变性以及AD的影响，使用体外和体内AD模型的发病机制。拟议的纵向研究增加了神经变性的血浆生物标志物与种族和民族多样性的梅萨队列，多组学数据、颈动脉血管和其他心脏代谢指标、脑成像、认知测试，和临床MCI/ADRD数据在中期到晚期的生命过渡期，再加上在体外和体内实验研究，有可能阐明动脉的贡献，刚度认知障碍，并确定分子和细胞机制，解释血管和早期AD/神经退行性病变的常见并发症并且可以作为改变疾病的干预措施的目标。