Progress in imaging techniques applied to the study of the glymphatic system

The glymphatic system is a brain-wide clearance pathway that maintains central nervous system homeostasis by facilitating cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange and metabolic waste removal. Accumulating evidence links glymphatic dysfunction to neurodegeneration, cerebrovascular disease, and sleep-related disorders, motivating the search for clinically deployable imaging biomarkers. Imaging has become central to this effort, spanning tracer-based approaches and non-invasive MRI methods such as phase-contrast magnetic resonance imaging (MRI), functional MRI-derived CSF dynamics, structural MRI markers including MRI-visible perivascular spaces and parenchymal CSF (pCSF) mapping, and diffusion-based indices including diffusion tensor image analysis along the perivascular space (DTI-ALPS). This review aims toprovide a translation-oriented perspective that reframes the current literature by disentangling what each modality actually measures-such as tracer transport, fluid compartment morphology and distribution, pulsatility-related motion, diffusion-sensitive exchange constraints, or vascular-interface perfusion/exchange physiology-from what it is often interpreted to represent (glymphatic clearance), and by proposing a practical roadmap to improve physiological specificity and clinical utility. Importantly, no truly non-invasive MRI technique can currently directly measure glymphatic transport or CSF-ISF exchange in humans, so existing readouts should be treated as surrogate markers with known confounds. We highlight emerging methods sensitive to slow flow and exchange and outline priorities for clinical translation, including harmonized protocols, cross-site reproducibility, mechanistic validation, and outcome-linked validation in prospective studies.