The Glymphatic System and Its Role in Neurovascular Diseases

Abstract

Over the past decade, clinicians and researchers have increasingly recognized the significance of the glymphatic system. Evidence demonstrates that this system-named for its reliance on astrocyte endfeet of glial cells and its lymphatic-like waste clearance function from the brain-is essential for regulating the accumulation and removal of amyloid aggregates and other interstitial waste products that may cause cognitive decline if not removed. Its activity is highly regulated, with flow driven by arterial wall pulsatility linked to the cardiac cycle, facilitating perivascular cerebrospinal fluid (CSF) influx into the brain interstitium and its efflux into the venous system. In the present review, we highlight the interplay between the glymphatic system and neurovascular diseases, as well as conditions that are currently being treated by endovascular means, including subarachnoid hemorrhage, idiopathic intracranial hypertension, steno-occlusive disease, and arteriovenous shunting diseases. We describe how changes in arterial pulsatility, disturbances in para-arterial CSF influx, changes in aquaporin-4 receptor composition, or venous hypertension with a decreased arteriovenous pressure gradient can cause dysfunction of different components of the glymphatic system, leading to similar clinical symptomatology with progressive cognitive decline that may be reversible.

Keywords: brain hydrodynamics; cerebrospinal fluid; glymphatic system; idiopathic intracranial hypertension; subarachnoid hemorrhage.

Fig. 1. Schematic overview of the glymphatic system. CSF egresses from the subarachnoid space into the brain interstitial space via the perivascular spaces. There, it collects waste products as it passes through the neuropil before draining into the perivenous spaces, the meningeal lymphatic system, and ultimately the deep cervical lymph nodes. (A) CSF is mainly produced by the choroid plexus. In the ventricle, exchange between CSF and ISF occurs along the ependymal cell layer. (B) CSF enters the periarterial space from the subarachnoid space, driven by arterial pulsatility, and then enters into the interstitium as ISF. There, it facilitates convective solute transport, followed by efflux into the perivenous space and subsequent drainage via arachnoid granulations into the SSS or via meningeal lymphatic vessels. (C) A close-up view of perivascular and parenchymal glymphatic flow. AQP4 is highly polarized to astrocytic endfeet abutting the perivascular space and, together with inter-endfoot gaps, facilitates CSF influx into the interstitium. Interstitial fluid and solutes subsequently undergo efflux via these structures toward the perivenous space. AQP4, aquaporin-4; CSF, cerebrospinal fluid; ISF, interstitial fluid; SSS, superior sagittal sinus

Fig. 2. Schematic presentation of the glymphatic system and pathophysiological mechanisms affecting it. AQP4, aquaporin-4; CSF, cerebrospinal fluid; IIH, idiopathic intracranial hypertension; SAH, subarachnoid hemorrhage

Fig. 3. Schematic representation of glymphatic dysfunction across various neurological conditions. Glymphatic flow can be disrupted through various mechanisms depending on the underlying pathology, including impaired CSF–ISF exchange, venous outflow restriction, and lymphatic drainage dysfunction. (A) SAH: blood products and inflammatory mediators in the subarachnoid space impair meningeal lymphatic drainage and glymphatic flow. Astrocytic AQP4 dysregulation further disrupts parenchymal CSF influx and efflux. (B) Idiopathic intracranial hypertension: inflammatory mediators increase CSF production via the choroid plexus, impair CSF absorption through arachnoid villi, and disrupt parenchymal CSF influx and efflux via AQP4 dysregulation. These alterations promote glymphatic congestion and raise intracranial pressure, leading to venous outflow restriction and reduced perivenous drainage. Lymphatic outflow is secondarily enhanced. (C) Cardiogenic and steno-occlusive diseases: reduced arterial pulsatility due to cardiac dysfunction or arterial stenosis diminishes periarterial CSF space and glymphatic inflow. (D) Shunting vascular diseases: elevated venous pressure and a reduced arteriovenous pressure gradient impair intracranial convective flow, disrupting glymphatic circulation. AQP4, aquaporin-4; CSF, cerebrospinal fluid; ICP, intracranial pressure; ISF, interstitial fluid; SAH, subarachnoid hemorrhage

Fig. 4. Proposed mechanism of glymphatic dysfunction in idiopathic intracranial hypertension. AQP4, aquaporin-4; CSF, cerebrospinal fluid; ICP, intracranial pressure