Quantitative Imaging of Brain Glymphatic Function in Humans

摘要 最近的免疫学和生理学研究提供了支持中枢神经的证据 脊椎动物的中枢神经系统(CNS)淋巴引流系统，最近被发现与 脑淀粉样β蛋白(Aβ)斑块清除障碍，如阿尔茨海默病(AD)相关性痴呆 (ADRD)。这个系统被认为包括：(I)硬脑膜和脑膜淋巴管，排出脑脊液和 间质液(ISF)向颈淋巴转移，并可能(Ii)与最近提出的 淋巴系统，一个水通道蛋白-4(AQP4)介导的系统，促进脑脊液-ISF从动脉周围流出到 静脉周围间隙，最终到达颈部淋巴管和结节。虽然多项独立研究 推测中枢淋巴系统可能与不明原因的清除情况有关 人类病因学(包括但不限于睡眠障碍、脑脊液清除障碍、多发性硬化症、 帕金森氏病和ADRD)，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。解决这个问题的关键障碍在于普遍缺乏成像。 可用于询问所建议的人类中枢神经系统淋巴系统的多个方面的方法 活着。因此，即使是关于这个系统如何随年龄、性别和行为状态变化的基本知识 仍然存在争议，这些限制排除了对患者病理特征的识别。就在最近， 我们已将先前工作中优化的非侵入性磁共振成像(MRI)方法 评估中枢神经系统的外周血液和淋巴循环功能障碍。我们有量化的衡量标准 61例老年帕金森病患者的颅内淋巴功能 认知功能障碍，并提供证据表明帕金森病患者有遗忘性轻度认知障碍 (AMCI)与年龄匹配的人相比，颅内淋巴功能的标志物显著降低 无aMCI的患者，淋巴血流速度的标记物与脑呈负相关 根据金标准β成像量化的PET负荷。这些发现为小说提供了一个基础， 非侵入性标记物可用于了解健康组织的淋巴功能，也可用于 存在大脑Aβ负担增加的情况。因此，这项工作的目标是应用新型磁共振成像并建立 PET方法评估(I)中枢神经系统淋巴系统如何随年龄和性别的变化而健康衰老，以及 随后中枢淋巴功能与(Ii)脑Aβ负荷和(Ii)行为状态的临床相关性 在有认知障碍的PD患者中，ADRD是公认的。研究结果将提供基本的见解 研究患有和不患有ADRD的人类中枢神经系统淋巴系统的行为。更广泛地说，这些方法 开发和完善将为寻求审问的越来越多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。

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.