Elsevier

The Lancet Neurology

Volume 17, Issue 11, November 2018, Pages 1016-1024
The Lancet Neurology

Rapid Review
The glymphatic pathway in neurological disorders

https://doi.org/10.1016/S1474-4422(18)30318-1Get rights and content

Summary

Background

The glymphatic (glial-lymphatic) pathway is a fluid-clearance pathway identified in the rodent brain in 2012. This pathway subserves the flow of CSF into the brain along arterial perivascular spaces and subsequently into the brain interstitium, facilitated by aquaporin 4 (AQP4) water channels. The pathway then directs flow 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 predominantly active during sleep, when the clearance of harmful metabolites such as amyloid β (Aβ) increases two-fold relative to the waking state. Glymphatic dysfunction, probably related to perturbed AQP4 expression, has been shown in animal models of traumatic brain injury, Alzheimer's disease, and stroke. The recent characterisations of the glymphatic and meningeal lymphatic systems in rodents and in humans call for revaluation of the anatomical routes for CSF–interstitial fluid flow and the physiological role that these pathways play in CNS health.

Recent developments

Several features of the glymphatic and meningeal lymphatic systems have been shown to be present in humans. MRI scans with intrathecally administered contrast agent show that CSF flows along pathways that closely resemble the glymphatic system outlined in rodents. Furthermore, PET studies have revealed 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 Alzheimer's disease compared with healthy controls. The observed reduction in CSF clearance was associated with increasing grey-matter concentrations of Aβ in the human brain, consistent with findings in mice showing that decreased glymphatic function leads to Aβ accumulation. Altered AQP4 expression is also evident in brain tissue from patients with Alzheimer's disease or normal pressure hydrocephalus; glymphatic MRI scans of patients with normal pressure hydrocephalus show reduced CSF tracer entry and clearance.

Where next?

Research is needed to confirm whether specific factors driving glymphatic flow in rodents also apply to humans. Longitudinal imaging studies evaluating human CSF dynamics will determine whether a causal link exists between reduced brain solute clearance and the development of neurodegenerative diseases. Assessment of glymphatic function after stroke or traumatic brain injury could identify whether this function correlates with neurological recovery. New insights into how behaviour and genetics modify glymphatic function, and how this function decompensates in disease, should lead to the development of new preventive and diagnostic tools and novel therapeutic targets.

Introduction

The mechanisms underlying solute clearance from the brain's extracellular space have puzzled neurologists for centuries.1 Protein aggregates are a common feature in patients with amyotrophic lateral sclerosis,2 Alzheimer's disease,3 Parkinson's disease,4 and other neurodegenerative diseases,4 implying that reduced clearance from the brain could be a shared phenomenon in neurodegeneration. Because the cerebral parenchyma is devoid of lymphatic vessels, the removal of protein waste from these tissues has traditionally been attributed to extracellular and intracellular degradation processes, including autophagy and ubiquitination,5, 6, 7 whereas a few proteins, such as amyloid β (Aβ), are also cleared by specific transport across the blood–brain barrier.8 Although transport of the interstitial fluid (ISF) within the brain parenchyma was traditionally attributed only to diffusion, several historical observations have revealed a lymphatic-like system that drains to the cervical lymphatics in the rodent brain, which might constitute an unappreciated, complementary aspect of brain clearance.9, 10, 11 Since 2012, two-photon microscopic studies of CSF flow in live murine brain have indicated the existence of the glymphatic pathway, a novel brain clearance mechanism with substantial capacity12, 13 (see panel for definitions of terms used in this Rapid Review).

In the glymphatic pathway, convective influx of CSF is balanced by perivenous efflux of ISF, which clears the neuropil of toxic proteinaceous metabolites, including Aβ.12 Glymphatic function robustly increases during sleep, thereby eliminating various metabolic byproducts from the extracellular space that accumulate during wakefulness.14 Clinical studies have shown CSF flow patterns in the human brain resembling that of the glymphatic pathway in rodents, and indicate that CSF clearance is reduced in patients with Alzheimer's disease or idiopathic normal pressure hydrocephalus.19, 20, 21 The elucidation of this newly described pathway in rodents enhances our basic understanding of brain clearance and presents a promising target for developing clinical tools for early risk assessment, diagnostics, prognostics, and therapeutics for neurodegenerative diseases. With a more detailed understanding of CSF flow pathways within and outside the brain, including the dural lymphatic network, a new understanding of CSF dynamics is emerging.22, 23, 24 This Rapid Review summarises the rapidly growing literature on CSF-mediated brain clearance in both humans and animal models, with emphasis on what is already known about clinical aspects of the human glymphatic pathway.

Section snippets

The glymphatic pathway

The glymphatic pathway is a highly organised fluid transport system that is currently best described in animal models. In the initial segments of the pathway, CSF from the subarachnoid space flows into the brain through the perivascular spaces of the large leptomeningeal arteries.12, 13, 22, 24 With branching of the vascular tree, CSF is driven into the brain parenchyma through the perivascular spaces of penetrating arteries, also known as Virchow–Robin spaces (figure 1).12, 25, 27 From the

Alzheimer's disease and other dementias

Accumulation of Aβ plaques and neurofibrillary tangles of hyperphosphorylated tau protein are implicated in the cognitive decline seen in Alzheimer's disease.51 Aβ, which has a physiological role in synaptic regulation and neuronal survival,52, 53 is degraded and cleared through multiple pathways.8 Findings from animal research suggest that the glymphatic pathway could be a substantial factor in the net clearance of Aβ.12, 17 Impaired glymphatic function in AQP4-knockout mice resulted in a 55%

Haemorrhagic stroke

Mouse models and a gyrencephalic non-human primate model of subarachnoid haemorrhage have shown impaired CSF inflow along periarterial influx routes starting 24 h after the injury.62, 63, 64 This glymphatic inhibition was attributed to the occlusion of perivascular spaces by blood components, specifically fibrin and fibrinogen deposits, as intraventricular delivery of the fibrinolytic tissue-type plasminogen activator restored CSF flow in these rodents (figure 4).62, 64 However, intracerebral

Traumatic brain injury

Traumatic brain injury (TBI) in mice leads to decreased glymphatic influx and impaired clearance of intracortically injected radiotracers from the brain interstitium, persisting for more than 28 days after the injury.67 Impaired glymphatic function in AQP4-knockout mice exacerbated the resultant accumulation of phosphorylated tau and axonal degeneration, processes that lead to cognitive decline, after TBI.67 Importantly, glymphatic efflux in the murine brain can transport biomarkers of TBI to

Conclusions and future directions

The characterisation of the structural and biochemical components of the glymphatic pathway in animals has brought new understanding of a highly organised fluid transport and clearance system in the CNS. The pathway entails a convective inflow of CSF within periarterial spaces and convective outflow of CSF–ISF towards perivenous spaces, which results in directional fluid flow through the brain parenchyma. Facilitated by polarised AQP4 expression on astrocytic endfeet, glymphatic flow rids the

Search strategy and selection criteria

We searched PubMed using the keywords “glymphatic”, “glial lymphatic”, “dural lymphatics”, “brain clearance”, and “perivascular spaces”. The search identified more than 2000 studies in rodents, non-human primates, and humans. Only studies published in English between Jan 1, 2015, and July 15, 2018, were included in this Rapid Review. Seminal papers relevant to the review that were published before January, 2015, were also included. The final reference list was generated on the basis of

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