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.

动脉僵硬是一种血管老化生物标志物，已成为重要的风险因素痴呆症，并在横截面与脑MRI测量神经变性和宠物测量的脑Aβ和Tau Burnen，成像阿尔茨海默氏病（AD）和广告相关痴呆症（ADRD）。但是，动脉刚度可能有助于认知障碍和痴呆症尚不完全理解。最近，几个等离子体包括磷酸化tau（p-tau）在内的生物标志物已成为有希望的替代物的 Aβ/tau pet burnen和神经变性。该应用的目的是表征广告病理/神经变性将动脉僵硬与使用血浆连接到认知障碍生物标志物，并识别血管的潜水员和重叠机制和重叠的机制通过以下目的与认知障碍相关的神经降级：A1。到量化AD/神经变性的血浆生物标志物，并确定基线和动脉刚度在血浆生物标志物变化上的进展。 A2。检查效果血管衰老的单核基因组特征（DNA甲基甲基组学和转录组学）。 A3。到检查单核细胞基因组特征对AD/血浆生物标志物变化的影响神经变性。 A4。测试SIRT1对血管和神经脱生和AD的影响使用体外和体内AD模型的发病机理。拟议的纵向研究增加了神经退行性的血浆生物标志物与种族和种族多样化的台面同伴多词数据，颈动脉血管和其他心脏代谢措施，脑成像，认知在整个中期至后期过渡期内进行测试以及临床MCI/ADRD数据，并与体外和体内实验研究有可能阐明动脉的贡献对认知障碍的刚度，并确定可以的分子和细胞机制解释血管和早期AD/神经退行性病理的常见共同发生并可以作为调整疾病的干预措施的目标。