The Glymphatic System in Neurological Diseases: Mechanisms, Imaging Surrogates, and Translational Uncertainties

This narrative review critically synthesizes mechanistic, imaging, and clinical evidence on the glymphatic system in neurological disease. It distinguishes direct tracer-based observations from indirect imaging surrogates and identifies the principal uncertainties that currently limit clinical translation.

The glymphatic framework describes glia-associated perivascular routes that support exchange between cerebrospinal fluid (CSF) and interstitial fluid and contribute to solute transport in experimental models. Rodent studies show that aquaporin-4 polarization, vascular pulsatility, and sleep state modulate tracer movement, but the relative contribution of convection, diffusion, and alternative clearance pathways remains debated. Sleep-wake state alters interstitial or CSF concentrations of amyloid-beta and tau; however, these changes reflect both clearance and activity-dependent production or release. Meningeal lymphatic vessels interact anatomically and functionally with CSF drainage pathways in preclinical models, whereas direct evidence for an integrated glymphatic-meningeal circuit in humans remains limited. Most human disease studies use cross-sectional or longitudinal associations derived from indirect imaging markers rather than direct measurements of glymphatic flow. Intrathecal contrast-enhanced magnetic resonance imaging provides a tracer-based assessment of CSF influx, distribution, and clearance to cervical lymph nodes. Diffusion tensor imaging along the perivascular space assesses water movement in the perivascular spaces, and phase-contrast MRI quantifies pulsatile CSF velocity and volume; both are noninvasive sequences. MRI-visible perivascular spaces, dynamic contrast-enhanced MRI, and CSF-hemodynamic coupling are indirect or partially overlapping measures of perivascular fluid biology. No noninvasive biomarker has yet been validated as a direct measure of human glymphatic flow. Candidate interventions including sleep-directed strategies, photobiomodulation, respiratory entrainment, gamma-frequency sensory stimulation, neuromodulation, and pharmacological approaches, remain preclinical or early mechanistic, and none has improved patient-important neurological outcomes through a validated glymphatic mechanism.