Quantitative Imaging of Brain Glymphatic Function in Humans

人类大脑类淋巴功能的定量成像

• 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
• 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' 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' 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

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.

摘要 最近的免疫学和生理学研究提供了支持中枢神经系统 中枢神经系统（CNS）淋巴引流系统在脊椎动物，这是最近牵连， 脑淀粉样蛋白β（Aβ）斑块清除障碍，如阿尔茨海默病（AD）相关痴呆 （ADRD）.该系统被认为包括（i）引流CSF的硬膜和脑膜淋巴管， 间质液（ISF）流向颈部淋巴结，可能（ii）与最近提出的 胶质淋巴系统，一种水通道蛋白4（AQP 4）介导的系统，促进CSF-ISF从动脉周围流出到 静脉周围空间并最终到达颈部淋巴管和淋巴结。虽然多项独立研究 我推测CNS淋巴系统可能与未知的清除条件有关， 人类的病因学（包括但不限于睡眠障碍，CSF清除障碍，多发性硬化， 帕金森病和ADRD），但关于该系统与这些疾病的相关性的直接信息有限 人类的疾病。解决这一问题的关键障碍在于普遍缺乏成像 这些方法可以应用于询问所提出的人CNS淋巴系统的多个方面， vivo.因此，即使是关于这个系统如何随着年龄、性别和行为状态而变化的基本知识， 仍然存在争议，这些局限性妨碍了对患者病理特征的识别。最近， 我们已经翻译了在之前的工作中优化的非侵入性磁共振成像（MRI）方法， 评估外周血和淋巴循环功能障碍到中枢神经系统。我们量化了 61例老年帕金森病（PD）患者的颅内胶质淋巴功能，伴或不伴相关 认知功能障碍，并提供证据表明，PD患者遗忘的轻度认知功能障碍， 与年龄匹配的患者相比，aMCI患者的颅内胶质淋巴功能标志物显着减少 没有aMCI的患者，并且胶质淋巴流速的标志物与脑组织的 从金标准PET成像中定量的Aβ负荷。这些发现提供了一个基础， 非侵入性标记物可用于了解健康组织中的淋巴功能， 存在脑Aβ负荷增加。因此，这项工作的目标是应用新的MRI和建立 PET方法用于评估（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，CNS淋巴功能对（ii）脑Aβ负荷和（ii）行为状态的临床相关性 在伴有认知损害的PD患者中，一种公认的ADRD。研究结果将提供基本的见解 在有和没有ADRD的人中CNS淋巴系统的行为。更广泛地说， 开发和完善将提供一个支持结构，越来越多的研究寻求询问 CNS淋巴功能，但目前的成像工具缺乏足够的灵敏度。