Map Paravascular Fluid Dynamic Signatures of Key Aging and AD Processes Using Dynamics Diffusion-Weighted Imaging

使用动力学扩散加权成像绘制关键衰老和 AD 过程的血管旁流体动态特征

• 批准号: 10739365
• 负责人: Qiuting Wen
• 金额: $ 231.79万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739365
• 关键词: Affect; Age; Aging; Agreement; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-Protein; Arteries; Biological Markers; Blood Vessels; Brain; Cerebrospinal Fluid; Circulation; Clinical; Cognitive; Data; Deposition; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease Pathway; Elasticity; Essential Hypertension; Functional disorder; Goals; Human; Hypertension; Imaging Techniques; Impaired cognition; Impairment; Indiana; Individual; Knowledge; Liquid substance; Longitudinal cohort; Maps; Measures; Monitor; Movement; Neurodegenerative Disorders; Outcome; Pathogenesis; Pathology; Pathway interactions; Pattern; Phenotype; Plasma; Positron-Emission Tomography; Principal Investigator; Process; Pump; Records; Reproducibility; Research; Risk; Rodent; Route; Scanning; Techniques; Time; Tracer; Woman; abeta accumulation; aged; apolipoprotein E-4; brain dysfunction; cardiovascular risk factor; cerebrospinal fluid flow; clinical database; cohort; genetic risk factor; glymphatic flow; glymphatic function; glymphatic system; healthy aging; image translation; imaging approach; imaging biomarker; men; neuroimaging; neurotoxic; non-invasive imaging; novel; novel therapeutics; pre-clinical; preclinical study; statistical learning; success; tau Proteins; tau aggregation; tool; vascular risk factor; wasting

Abstract Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) and tau pathologies. Mounting evidence from preclinical studies suggests that disruption of the paravascular cerebrospinal fluid (pCSF) clearance pathway (glymphatic system) contributes to Aβ and tau aggregation. These studies further highlighted a reliance of pCSF circulation on vascular functions, where spontaneous hypertension led to reduced pCSF flow. However, it is unclear whether similar phenomena exist in humans and how pCSF dynamics change with aging, essential hypertension, and AD. Human studies of the glymphatic system have proven to be challenging due to the lack of safe tracer-free imaging approaches. Recently, a novel clinically feasible imaging technique, dynamic diffusion-weighted imaging (dDWI), has been developed by the PI, which yields reproducible quantitative metrics of pCSF movement within the glymphatic system. The quantitative metrics can simultaneously assess the volume and dynamics of pCSF near the major and pial arteries – the influx of the glymphatic flow. As one of the early human studies in this glymphatic pathway, our results of a cohort aged 18 to 82 revealed significantly enlarged paravascular space and remarkably altered pCSF pumping in the older brain, the extent of which is associated with cognitive decline. Built upon the novel technique, intriguing preliminary results, and our team’s strong expertise in AD research, the overall goal of the proposal is to map pCSF signatures of key aging and AD processes. Our central hypothesis is that although aging and hypertension are two culprits of compromised pCSF, AD show disease-specific pCSF abnormalities related to pathogenesis. We will leverage the state-of-the-art neuroimaging techniques (e.g., dDWI, Aβ/tau positron emission tomography [PET]) and our large longitudinal clinical database of the Indiana Alzheimer’s Disease Research Center (IADRC) to achieve the following aims: (1) Map pCSF signatures of healthy aging. (2) Map pCSF signatures of aging with hypertension. (3) Map pCSF signatures of AD and determine their associations with Aβ/tau aggregation. The success of the three aims will determine whether fluid clearance function shows similar or distinct alterations in healthy aging, hypertension, and AD. Such knowledge is critical for identifying disease pathways and developing novel therapeutics. The new imaging technique is expected to provide valuable and translational imaging biomarkers for detecting and monitoring dysfunctional fluid clearance in AD and be applied to study other neurodegenerative diseases of high clinical impact.

抽象的 阿尔茨海默氏病（AD）的特征是淀粉样蛋白β（Aβ）和TAU的积累 病理。临床前研究的越来越多的证据表明，破坏了 毛道脑脊液（PCSF）清除途径（淋巴系统）有助于 Aβ和Tau聚集。这些研究进一步强调了PCSF循环的保留 血管功能，赞助高血压导致PCSF流量减少。但是，是 尚不清楚人类中是否存在类似现象以及PCSF动态如何随着衰老而变化， 基本高血压和广告。人类对糖基系统的研究已被证明是 由于缺乏安全的无示踪影像方法，具有挑战性。最近，一部小说在临床上 可行的成像技术，动态扩散加权成像（DDWI）已通过 PI产生糖中PCSF运动的可再现定量指标 系统。定量指标可以简单地评估PCSF的体积和动力学 靠近主要动脉和伴侣动脉 - 糖流动的影响。作为早期的人之一 在这种糖基途径中的研究，我们的18至82岁的队列结果显着显示 大脑中的PCSF泵送的链血管空间扩大，程度很大 其中与认知能力下降有关。建立在新技术的基础上，引人入胜的初步 结果以及我们团队在广告研究方面的强大专业知识，该提案的总体目标是映射 关键衰老和广告过程的PCSF签名。我们的中心假设是，尽管老化 高血压是受损PCSF的两个罪魁祸首，广告显示了疾病特异性的PCSF 异常与发病机理有关。我们将利用最新的神经影像 技术（例如DDWI，Aβ/TAU正电子发射断层扫描[PET]）和我们的大纵向 印第安纳州阿尔茨海默氏病研究中心（IADRC）的临床数据库 以下目的：（1）映射健康衰老的PCSF特征。 （2）与衰老的PCSF签名 高血压。 （3）映射AD的PCSF签名并确定其与Aβ/TAU的关联 聚合。这三个目标的成功将确定流体清除功能是否显示 健康衰老，高血压和AD的类似或不同的改变。这样的知识至关重要 用于识别疾病途径并开发新的治疗。新成像技术 预计将提供有价值和翻译的成像生物标志物来检测和监测 AD中功能失调的流体清除率，可用于研究其他神经退行性疾病 高临床影响。