CSF clearance through arachnoid fenestrations to olfactory meningeal lymphatics

Abstract

Meningeal (dural) lymphatics are essential for cerebrospinal fluid (CSF) clearance to cervical lymph nodes, yet the precise pathway is incompletely understood. Using a multifaceted approach in mice, we examined tracer dynamics and the CSF outflow pathway from the subarachnoid space (SAS) to the nasal mucosa and identified a discrete arachnoid region surrounding the olfactory bulbs with abundant fenestrations. Similar arachnoid fenestrations were found in cynomolgus monkeys. Fluorescent tracers in the SAS passed through arachnoid fenestrations into dural lymphatics, which traversed the cribriform plate foramina, joined the nasal lymphatics, and drained to the cervical lymph nodes. In aged mice, the known reduction in CSF outflow was accompanied by lymphatic atrophy in the olfactory dura and nasal mucosa and by fewer arachnoid fenestrations and smaller cribriform plate foramina. Importantly, the lymphatics and CSF clearance were restored to normal by intranasal delivery of vascular endothelial growth factor-C (VEGF-C), thereby documenting the reversibility of the aging-related impairment in CSF clearance.