New integrated three-interface conceptual model for clearance and immune surveillance in the human CNS.

The central nervous system (CNS) lacks a classical lymphatic system and instead relies on cerebrospinal fluid (CSF) circulation for metabolic waste removal and for defense/immune surveillance. Recent research has consolidated the concept of an integrated glymphatic-lymphatic continuum (because of the relevant contribution of glial cells), where CSF acts as a central transport medium linking parenchymal exchange with meningeal lymphatic outflow. Within this framework, the glymphatic system supports CSF-interstitial fluid exchange, particularly during sleep, when vascular pulsatility enhances solute clearance. Translating insights from rodent systems to the human brain, however, requires explicit consideration of the subarachnoid space and CSF hydrodynamics as an intermediate interface that distributes CSF and modulates the balance between parenchymal influx and efflux toward dural lymphatics. We here propose a three-phase conceptual model comprising: (1) a microscale segment that includes perivascular spaces, the neuropil/interstitial compartment, glial elements, and aquaporin-mediated water transport; (2) a mesoscale segment centered on the arachnoid barrier and the subarachnoid CSF compartment, functioning as a distribution and exchange interface; and (3) a macroscale segment encompassing arachnoid granulations and dural meningeal lymphatic vessels as the principal egress pathways. To further support this with a clinical perspective, we review evolutionary adaptations that have resulted in more efficient fluid exchange between CSF reservoirs and the extracellular space of the human brain. This three-interface framework may improve diagnostic and therapeutic precision by recognizing that the distinct disorders, such as neurodegenerative proteinopathies, cerebral edema, hydrocephalus, or meningoencephalitis, preferentially disrupt specific interfaces across scales.