EXPRESS: Glymphatic System Dysfunction and Neurological Disorders: From Mechanisms to Therapeutic Strategies

Traditional neuroanatomy long asserted the absence of lymphatic circulation in the central nervous system, contradicting its high metabolic activity and efficient waste removal. This paradox was resolved in the 21st century by Iliff et al., who discovered the glymphatic system (GS)-a glia-dependent network enabling cerebrospinal fluid to flow through periarterial spaces, clear interstitial waste via paravenous pathways, and drain into peripheral circulation through meningeal/cranial lymphatic routes. Beyond waste clearance, the GS mediates nutrient distribution and neuroactive signaling, fundamentally reshaping brain homeostasis concepts. Critically, emerging evidence reveals bidirectional links between glymphatic dysfunction and neurological diseases: impaired fluid dynamics both triggers and aggravates neurodegeneration and cerebrovascular pathologies through self-amplifying neuroinflammation and pathological protein accumulation. Existing reviews, focus narrowly on isolated mechanisms or pathologies, lacking systematic analysis of these bidirectional interactions or comprehensive therapeutic evaluations. Here, we synthesize current knowledge on GS anatomy, functional regulators, and assessment techniques. We critically examine bidirectional GS-disease relationships, emphasizing disrupted fluid dynamics in neurodegeneration, cerebrovascular pathology, and neuroinflammation. Furthermore, we evaluate emerging GS-targeted therapies, discussing their translational potential and limitations. By integrating basic and clinical perspectives, this study advances a unified framework for understanding neuropathological mechanisms and developing novel interventions targeting glymphatic pathways.