Quantitative Imaging of Brain Glymphatic Function in Humans

人类大脑类淋巴功能的定量成像

基本信息

批准号：
10569545
负责人：
Daniel Oliver Claassen
金额：
$ 60.66万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569545
关键词：
Address Adult Age Aging Alzheimer&apos s disease related dementia Amyloid beta-Protein Anesthesia procedures Behavior Behavioral Blood Blood Vessels Brain Brain imaging Brain region Central Nervous System Cervical Cervical lymph node group Clinical Communication Coupling Data Deep Brain Stimulation Disease Elderly Enrollment Ependymal Cell Etiology Foundations Functional disorder Goals Head and neck structure Health Healthcare Human Image Imaging Device Immunologics Impaired cognition Intercellular Fluid Investigation Kinetics Knowledge Link Liquid substance Longevity Lymph Lymph Node Dissections Lymphatic Lymphatic System Lymphatic function Magnetic Resonance Imaging Measurement Measures Mediating Meningeal lymphatic system Methods Multiple Sclerosis Neurobehavioral Manifestations Neurons Parkinson Disease Participant Pathologic Patients Performance Perfusion Peripheral Physiological Physiology Positron-Emission Tomography Production Propofol Reproducibility Rest Sedation procedure Sleep Disorders Stroke Structure Structure of choroid plexus Subgroup Symptoms System Tissues Translating Venous Vertebrates Visualization Wakefulness Work abeta accumulation alpha synuclein amnestic mild cognitive impairment animal data aquaporin 4 awake biological sex bone brain parenchyma brain tissue clinical phenotype clinically relevant cognitive impairment in Parkinson&apos s glymphatic flow glymphatic function glymphatic system healthy aging hemodynamics imaging approach imaging modality improved in vivo insight lymph flow lymph nodes lymphatic circulation lymphatic drainage lymphatic dysfunction lymphatic vasculature lymphatic vessel motor symptom neuropathology novel peer peripheral blood protein aggregation quantitative imaging response sex β-amyloid burden

项目摘要

ABSTRACT Recent immunological and physiological studies have provided evidence in support of a central nervous system (CNS) lymphatic drainage system in vertebrate animals, which has more recently been implicated in brain amyloid beta (Aβ) plaque clearance disorders such as Alzheimer's disease (AD)-related dementias (ADRD). This system is believed to comprise (i) dural and meningeal lymphatic vessels that drain CSF and interstitial fluid (ISF) toward cervical lymph nodes and which may (ii) communicate with the recently-proposed glymphatic system, an aquaporin-4 (AQP4)-mediated system that facilitates CSF-ISF efflux from periarterial to perivenous spaces and ultimately to cervical lymphatic vessels and nodes. While multiple independent studies have speculated that the CNS lymphatic system may have relevance to clearance conditions of unknown etiology in humans (including but not limited to sleep disorders, CSF clearance disorders, multiple sclerosis, Parkinson's disease, and ADRD), limited direct information is available on the relevance of this system to these disorders in humans. The critical barrier to addressing this problem rests with a general lack of imaging methods that can be applied to interrogate multiple aspects of the proposed human CNS lymphatic system in vivo. As such, even basic knowledge about how this system changes with age, sex, and behavioral state remain debated, and these limitations preclude identification of pathological features in patients. Very recently, we have translated non-invasive magnetic resonance imaging (MRI) methods optimized in prior work for evaluating peripheral blood and lymphatic circulatory dysfunction to the CNS. We have quantified measures of intracranial glymphatic function in 61 older adults with Parkinson's disease (PD), with and without associated cognitive dysfunction, and have provided evidence that PD patients with amnestic mild cognitive impairment (aMCI) have significantly reduced markers of intracranial glymphatic function compared to age-matched patients without aMCI, and also that markers of glymphatic flow velocity inversely correlate with brain Aβ burden quantified from gold-standard PET imaging. These findings provide a foundation in which novel, non-invasive markers can be applied to understand lymphatic function in healthy tissue and also in the presence of increased brain Aβ burden. As such, the goal of this work is to apply novel MRI and established PET approaches to evaluate (i) how the CNS lymphatic system varies with age and sex for healthy aging, and subsequently the clinical relevance of CNS lymphatic function on (ii) brain Aβ burden and (ii) behavioral state in PD patients with cognitive impairment, a recognized ADRD. Study findings will provide fundamental insights into the behavior of the CNS lymphatic system in humans with and without ADRD. More broadly, the methods developed and refined will provide a support structure for the growing number of studies seeking to interrogate CNS lymphatic function, but where current imaging tools lack sufficient sensitivity.

抽象的最近的免疫学和物理研究提供了支持中枢神经系统的证据脊椎动物中的系统（CNS）淋巴引流系统，最近与该动物有关脑淀粉样β（Aβ）斑块清除率（例如阿尔茨海默氏病）（AD）相关痴呆症（ADRD）。据信，该系统会构建（i）消耗CSF和脑膜淋巴的硬膜和脑膜淋巴视频间质液（ISF）朝向宫颈淋巴结，并且可能（ii）与最近共同传播 Glymphatic System，Aquaporin-4（AQP4）介导的系统，可促进CSF-FISF外排有孔的空间，最终用于宫颈淋巴视频和节点。而多个独立研究已经推测CNS淋巴系统可能与未知的清除条件相关人类病因（包括但不限于睡眠障碍，CSF清除障碍，多发性硬化症，帕金森氏病和ADRD），有限的直接信息可获得有关该系统与这些系统的相关性人类的疾病。解决此问题的关键障碍是普遍缺乏想象力可以应用于询问拟议人类中枢神经系统淋巴系统多个方面的方法体内。因此，即使是关于该系统如何随着年龄，性别和行为状态变化的基本知识仍有争议，这些局限性排除了患者病理特征的鉴定。最近，我们已经翻译了在先前工作中优化的非侵入性磁共振成像（MRI）方法评估向CNS的外周血和淋巴回路功能障碍。我们已经量化了帕金森氏病（PD）的61名老年人的颅内糖性功能，有和没有相关性认知功能障碍，并提供了证据表明最轻度认知障碍的PD患者（AMCI）与年龄匹配相比，颅内糖的标记显着降低没有AMCI的患者，以及糖流速速度的标记与大脑成反比通过金标准的宠物成像量化的Aβ燃烧。这些发现为小说提供了基础可以应用非侵入性标记物来了解健康组织中的淋巴功能大脑AβBurnen的存在。因此，这项工作的目的是应用新颖的MRI并确定评估（i）CNS淋巴系统如何随着年龄和性别而变化的PET方法随后，CNS淋巴功能在（ii）脑Aβ燃烧和（ii）行为状态上的临床相关性在认知障碍的PD患者中，公认的ADRD。研究发现将提供基本的见解进入有或没有ADRD的人类中CNS淋巴系统的行为。更广泛地，方法开发和完善的将为越来越多的研究提供支持结构 CNS淋巴功能，但是当前的成像工具缺乏足够的灵敏度。