The glymphatic pathway in neurological disorders

Abstract

Background The glial-lymphatic or glymphatic pathway is a fluid clearance pathway recently identified in the rodent brain. This pathway subserves the flow of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and thence into the brain interstitium facilitated by aquaporin-4 (AQP4) water channels. The pathway then directs flows towards the venous perivascular and perineuronal spaces, ultimately clearing solutes from the neuropil into meningeal and cervical lymphatic drainage vessels. In rodents, the glymphatic pathway is primarily active during sleep, when the clearance of harmful metabolites such as amyloid β (Aβ) increases two-fold relative to the waking state. Glymphatic dysfunction has been demonstrated in animal models of traumatic brain injury (TBI), Alzheimer’s disease (AD) and micro-infarct disease, most likely in relation to perturbed expression of AQP4. The recent characterizations of the glymphatic and meningeal lymphatic systems calls for revaluation of the anatomical routes for CSF-ISF flow and the physiological role that these pathways play in CNS health. Recent developments Recent work has revealed that several features of the glymphatic and meningeal lymphatic systems are also present in humans. MRI imaging of intrathecally-administered contrast agent shows that CSF flows along pathways closely resembling the glymphatic system outlined in rodents. Furthermore, PET studies reveal that Aβ accumulates in the healthy brain after a single night of sleep deprivation, suggesting that the human glymphatic pathway might also be primarily active during sleep. Other PET studies have shown that CSF clearance of Aβ and tau tracers is reduced in patients with AD compared to healthy controls. The observed reduction in CSF clearance was associated with increasing grey matter Aβ levels in human brain, which is consistent with findings in mice showing that decreased glymphatic function leads Aβ accumulation. Altered AQP4 expression is also evident in brain tissue from AD or normal pressure hydrocephalus (NPH) patients; glymphatic MRI of NPH patients shows reduced CSF tracer entry and clearance. Where next? Future research is needed to confirm if specific factors driving glymphatic flow in rodents also apply to humans. Conducting longitudinal imaging studies to evaluate human CSF dynamics will determine if there is indeed a causal link between reduced brain solute clearance and the development of neurodegenerative diseases. Assessment of glymphatic function after stroke or TBI could identify if it correlates with neurological recovery. Gaining new insights into how behavior and genetics modify glymphatic function, and how this decompensates in disease should lead to the development of new preventive and diagnostic tools, as well as novel therapeutic targets.

Pattern and severity of transverse sinus stenosis in patients with pulsatile tinnitus associated with sigmoid sinus wall anomalies

“…Furthermore, although transverse sinus diameter alone is not an adequate proxy for posterior fossa venous outflow, quantitative methods for measuring overall and segmental posterior fossa venous outflow are still not available. Numerous alternative pathways exist, including the occipital sinuses; occipital emissary veins; suboccipital venous plexus; a petrosquamous sinus; condylar veins and others that could play a role; as well as meningeal lymphatics and glymphatics, which are not visible at all with conventional imaging . A dynamic, flow‐based method that accounted for all possible alternative pathways would allow for systematic comparison between different cohorts of subjects.…”

Clinical and experimental aspects of aneurysmal subarachnoid hemorrhage

“…To note, the recently described glial‐lymphatic or glymphatic pathway, a fluid clearance pathway that subserves the flow of CSF into the brain along arterial perivascular spaces, has been found to be impaired in SAH . There appears to be impaired CSF inflow starting at 24 hours after the insult attributed to the occlusion of perivascular spaces by blood components . This could represent another target that warrants investigation in animal models of SAH.…”

“…166 There appears to be impaired CSF inflow starting at 24 hours after the insult attributed to the occlusion of perivascular spaces by blood components. 167 This could represent another target that warrants investigation in animal models of SAH.…”

Meningeal lymphatic network: The middleman of neuroinflammation

“…[7][8][9]31,40 Several modalities can be investigated; for example, previous studies have already shown that inflammation can induce several pathways associated with lymphatic vessel remodeling and lymphangiogenesis. The discovery of meningeal lymphatic and glymphatic networks in the CNS represents a new and unexplored therapeutic target.…”