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：
10394784
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/10394784
关键词：
Abeta clearance Address Adult Age Aging Alzheimer&apos s disease related dementia Amyloid beta-Protein Anesthesia procedures Behavior Behavioral Blood Blood Vessels Brain Brain imaging Cervical Cervical lymph node group Clinical Conflict (Psychology)Coupling Data Deep Brain Stimulation Disease Elderly Enrollment Ependymal Cell Etiology Foundations Functional disorder Goals Gold Head and neck structure Health Healthcare Human Image Imaging Device Immunologics Impaired cognition Intercellular Fluid Investigation 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 Neuraxis Neurobehavioral Manifestations Neurons Parkinson Disease Participant Pathologic Patients Performance Perfusion Peripheral Physiological Physiology Positron-Emission Tomography Production Propofol Reproducibility Rest Senile Plaques Sleep Disorders Stroke Structure Structure of choroid plexus Subgroup Symptoms System Tissues Translating Vertebrates 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生理学研究提供了支持中枢神经系统的证据脊椎动物的淋巴引流系统（CNS），最近与大脑β淀粉样蛋白 (Aβ) 斑块清除障碍，例如阿尔茨海默病 (AD) 相关的痴呆症 (ADRD) 该系统被认为包括 (i) 排出脑脊液和脑脊液的硬脑膜和脑膜淋巴管。间质液（ISF）流向颈部淋巴结，并且可以（ii）与最近提出的类淋巴系统，一种水通道蛋白 4 (AQP4) 介导的系统，可促进 CSF-ISF 从动脉周围流出到经多项独立研究，最终到达颈部淋巴管和淋巴结。推测中枢神经系统淋巴系统可能与未知的清除条件有关人类病因（包括但不限于睡眠障碍、脑脊液清除障碍、多发性硬化症、帕金森病和 ADRD），关于该系统与这些疾病的相关性的直接信息有限。解决人类疾病的关键障碍在于普遍缺乏成像技术。可用于询问所提出的人类中枢神经系统淋巴系统的多个方面的方法因此，甚至包括有关该系统如何随年龄、性别和行为状态变化的基本知识。仍然存在争议，并且这些限制最近阻碍了对患者病理特征的识别。我们已经将之前工作中优化的非侵入性磁共振成像 (MRI) 方法转化为评估中枢神经系统的外周血和淋巴循环功能障碍。 61 名患有帕金森病 (PD) 的老年人的颅内淋巴功能，无论有无相关认知功能障碍，并提供证据表明 PD 患者存在轻度遗忘障碍 (aMCI) 与年龄匹配的人相比，颅内类淋巴功能标记物显着减少没有 aMCI 的患者，并且类淋巴流速标记物与大脑呈负相关通过黄金标准 PET 成像量化 Aβ 负荷，为新的、非侵入性标记物可用于了解健康组织以及身体中的淋巴功能因此，这项工作的目标是应用新的 MRI 并建立。 PET 方法可评估 (i) CNS 淋巴系统如何随年龄和性别变化以实现健康老龄化，以及随后研究中枢神经系统淋巴功能对 (ii) 大脑 Aβ 负荷和 (ii) 行为状态的临床相关性对于患有认知障碍的 PD 患者，一项公认的 ADRD 研究结果将提供基本见解。更广泛地说，这些方法对患有和不患有ADRD的人的中枢神经系统淋巴系统的行为进行了研究。的发展和完善将为越来越多的寻求质疑的研究提供支持结构中枢神经系统淋巴功能，但目前的成像工具缺乏足够的灵敏度。