Resolving the mysteries of brain clearance and immune surveillance
Jonathan Kipnis, Helene Benveniste, Anne Eichmann, Jean‐Léon Thomas, Daniel S. Reich, Laura D. Lewis, Li-Huei Tsai, Antoine Drieu, Erik N.T.P. Bakker, Douglas H. Kelley, Iben Lundgaard, Humberto Mestre, Benedikt Zott, Per Kristian Eide, Matthias J.P. van Osch, Susanne J. van Veluw, Jeffrey J. Iliff, Andrew C. Yang, Laura Santambrogio, Sandro Dá Mesquita, Richard Daneman, Justin Rustenhoven, Steven A. Goldman, Maiken Nedergaard
Abstract
Recent advances are transforming our understanding of brain fluid dynamics, highlighting cerebrospinal fluid (CSF) flow as a key process in brain waste clearance. While debates persist regarding its anatomical pathways and regulatory mechanisms, certain core principles have become widely accepted. CSF influx occurs primarily along periarterial spaces, solute clearance follows multiple routes, and glymphatic and meningeal lymphatic systems are functionally connected. Brain clearance is influenced by vascular pulsation, neural activity, and sleep. Immune cells at brain-border niches both monitor solute efflux and modulate flow, linking brain clearance to neuroimmune interactions. A deeper understanding of brain clearance could unlock new therapeutic avenues for autoimmune, neurodegenerative, neoplastic, and psychiatric disorders.