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.

动脉僵硬度是一种血管老化生物标志物，已成为心血管疾病的重要危险因素。痴呆症，并且与大脑 MRI 测量的神经退行性变有关 PET 测量大脑 Aβ 和 Tau 负荷、阿尔茨海默病 (AD) 和然而，动脉硬化可能导致 AD 相关痴呆 (ADRD) 的机制。最近，一些血浆对认知障碍和痴呆的影响尚不完全清楚。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品 Aβ/Tau PET 负担和神经退行性疾病此应用的目标是表征 AD。使用血浆将动脉僵硬度与损伤联系起来的病理学/神经变性生物标志物，并识别血管和疾病背后的多样化和重叠机制通过以下目标与认知障碍相关的神经变性：A1。 AD/神经变性的血浆定量生物标志物，以及基线和神经退行性变的影响确定动脉硬化对血浆生物标志物变化的影响。单核细胞基因组特征（DNA 甲基组学和转录组学）对血管衰老的影响 A3。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 A4. 测试 SIRT1 对血管和神经变性以及 AD 的影响。拟议的纵向研究添加了体外和体内AD模型的发病机制。种族和民族多样化 MESA 队列中神经退行性变的血浆生物标志物多组学数据、颈动脉血管和其他心脏代谢指标、脑成像、认知中年到晚年过渡期的测试和临床 MCI/ADRD 数据，再加上体外和体内实验研究，有可能阐明动脉的贡献认知障碍的僵化并确定可以的分子和细胞机制解释血管和早期 AD/神经退行性病理学的常见同时发生并可以作为疾病缓解干预措施的目标。