Brain-associated Lymphatic Vessels: From Historical Controversy to Meningeal Confirmation and Intracerebral Hypotheses

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BSTRACT

The brain was long described as an organ without classical lymphatic vessels, a view reinforced by the blood–brain barrier and the concept of central nervous system immune privilege. This dogma changed after molecular and imaging studies in 2015 established a functional dural/meningeal lymphatic network that drains cerebrospinal fluid, macromolecules, and immune cells toward cervical lymph nodes. Subsequent work extended these observations to humans and nonhuman primates, refined the skull base drainage routes, and connected meningeal lymphatics with aging, neuroinflammation, tumors, stroke, and neurodegeneration. A newer and more controversial question is whether lymphatic-like vessels also exist within deep brain parenchyma. Recent studies, including Tamadon et al . (2025), reported LYVE1-, PROX1-, VEGFC-, CD31-, and CD34-associated structures in mouse cortex, thalamus, and hippocampus, supporting a broader neurovascular–glymphatic–lymphatic interface. This review synthesizes the historical, anatomical, functional, and translational evidence for brain-associated lymphatic vessels from early anatomy to 2026. We distinguish established meningeal lymphatics from emerging intracerebral lymphatic-like structures, summarize methodological standards for vessel identification, and propose a cautious framework for future validation. The most defensible current model is not a lymphatic-free brain, nor yet a fully mapped parenchymal lymphatic network, but a dynamic continuum in which vascular entry, glymphatic exchange, meningeal lymphatic outflow, and possible deep lymphatic-like structures cooperate in brain homeostasis and disease.