神经退行性疾病中的脑脊液流出通路：鼻咽淋巴管与眼类类淋巴轴

文献信息

中文摘要

类淋巴系统支持脑脊液（CSF）与组织间液（ISF）之间的交换，并被认为在不同程度上参与淀粉样蛋白β（Aβ）、tau、乳酸及其他溶质的转运或清除。尽管大多数研究集中于脑脊液流入、星形胶质细胞水通道蛋白4（AQP4）表达、血管周围定位与极化、AQP4介导的跨膜水转运以及血管周围交换，脑清除还依赖于含废物液体的有效颅外引流。在这篇叙述性综述中，我们考察这一“流出端”，包括脑膜淋巴管、筛板-嗅-鼻黏膜通路、颅神经周围间隙、鼻咽淋巴丛、颈部淋巴管及颈深淋巴结。我们强调颅底和鼻咽淋巴丛是颅内脑脊液与颅外淋巴引流之间的潜在界面，并评估关于整体液体与通用示踪剂转运、可溶性蛋白清除、聚集蛋白处理及免疫抗原引流的通路特异性和货物特异性证据。我们还考虑针对淋巴管收缩性、VEGF-C-VEGFR3信号、机械刺激、压力梯度、AQP4介导的跨膜水转运以及实验观察到的光诱导瞳孔调节的实验策略。全文强调，针对包括Aβ、tau和α-突触核蛋白在内的各具体货物的证据在不同解剖通路间并不均衡，且仍以临床前或间接证据为主。未来需要整合高分辨率淋巴成像、功能性生物标志物以及纵向或干预性设计的研究，以确定脑脊液流出改变是神经退行性变的后果、疾病进展的促进因素，还是神经退行性疾病中一个可能可干预的过程。

英文摘要

The glymphatic system supports cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and has been implicated, to different extents, in the transport or clearance of amyloid-β (Aβ), tau, lactate and other solutes. Although most studies have focused on CSF influx, astrocytic aquaporin 4 (AQP4) expression, perivascular localisation and polarisation, AQP4-mediated transmembrane water transport, and perivascular exchange, brain clearance also depends on efficient extracranial drainage of waste-containing fluid. In this narrative Review, we examine this 'outflow end', including meningeal lymphatic vessels, the cribriform plate-olfactory-nasal mucosal route, cranial perineural spaces, the nasopharyngeal lymphatic plexus, cervical lymphatic vessels and deep cervical lymph nodes. We highlight the skull base and nasopharyngeal lymphatic plexus as potential interfaces between intracranial CSF and extracranial lymphatic drainage and evaluate the route- and cargo-specific evidence for bulk-fluid and generic-tracer transport, soluble-protein clearance, aggregated-protein handling and immune-antigen drainage. We also consider experimental strategies targeting lymphatic contractility, VEGF-C-VEGFR3 signalling, mechanical stimulation, pressure gradients, AQP4-mediated transmembrane water transport and experimentally observed light-induced pupillary modulation. Throughout, we emphasise that evidence for individual cargoes, including Aβ, tau and α-synuclein, is uneven across anatomical routes and remains predominantly preclinical or indirect. Future studies integrating high-resolution lymphatic imaging, functional biomarkers and longitudinal or interventional designs are needed to determine whether altered CSF outflow is a consequence of neurodegeneration, a contributor to disease progression or a potentially modifiable process in neurodegenerative disease.