Cerebral edema is a severe complication of stroke linked to glymphatic system malfunction


Cerebral edema, swelling that occurs in the brain, is a severe and potentially fatal complication of stroke.

New research, which was conducted in mice and appears in the journal Science, shows for the first time that the glymphatic system – normally associated with the beneficial task of waste removal – goes awry during a stroke and floods the brain, triggering edema and drowning brain cells.

“These findings show that the glymphatic system plays a central role in driving the acute tissue swelling in the brain after a stroke”, said Maiken Nedergaard, M.D., D.M.Sc., co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine and senior author of the article.

“Understanding this dynamic – which is propelled by storms of electrical activity in the brain – point the way to potential new strategies that could improve stroke outcomes.”

First discovered by the Nedergaard lab in 2012, the glymphatic system consists of a network that piggybacks on the brain’s blood circulation system and is comprised of layers of plumbing, with the inner blood vessel encased by a ‘tube’ that transports cerebrospinal fluid (CSF). The system pumps CSF through brain tissue, primarily while we sleep, washing away toxic proteins and other waste.

While edema is a well-known consequence of stroke, there are limited treatment options and the severity of swelling in the brain depends upon the extent and location of the stroke.

Because the brain is trapped in the skull, it has little room to expand. If the swelling is severe, it can push in on important structures such as the brainstem, which regulates the cardiovascular and respiratory systems, resulting in death.

In extreme cases and often as a last resort, surgeons will remove a part of the skull to relieve the pressure on the brain.

Prior to the findings of the new study, it has been assumed that the source of swelling was the result of fluid from blood.

An electrical wave, then the flood

Ischemic stroke, the most common form of stroke, occurs when a vessel in the brain is blocked. Denied nutrients and oxygen, brain cells become compromised and depolarize – often within minutes of a stroke.

As the cells release energy and fire, they trigger neighboring cells, creating a domino effect that results in an electrical wave that expands outward from the site of the stroke, called spreading depolarization.

As this occurs, vast amounts of potassium and neurotransmitters released by neurons into the brain. This causes the smooth muscles cells that line the walls of blood vessels to seize up and contract, cutting off blood flow in a process known as spreading ischemia.

CSF then flows into the ensuing vacuum, inundating brain tissue and causing edema. The already vulnerable brain cells in the path of the flood essentially drown in CSF and the brain begins to swell.

These depolarization waves can continue in the brain for days and even weeks after the stroke, compounding the damage.

“When you force every single cell, which is essentially a battery, to release its charge it represents the single largest disruption of brain function you can achieve – you basically discharge the entire brain surface in one fell swoop,” said Humberto Mestre, M.D., a Ph.D. student in the Nedergaard lab and lead author of the study.

“The double hit of the spreading depolarization and the ischemia makes the blood vessels cramp, resulting in a level of constriction that is completely abnormal and creating conditions for CSF to rapidly flow into the brain.”

Prior to the findings of the new study, it has been assumed that the source of swelling was the result of fluid from blood.

The study correlated the brain regions in mice vulnerable to this post-stroke glymphatic system dysfunction with edema found in the brains of humans who had sustained an ischemic stroke.

Pointing the way to new stroke therapies

The findings suggest potential new treatment strategies that used in combination with existing therapies focused on restoring blood flow to the brain quickly after a stroke. The study could also have implications for brain swelling observed in other conditions such as subarachnoid hemorrhage and traumatic brain injury.

Approaches that block specific receptors on nerve cells could inhibit or slow the cycle of spreading depolarization. Additionally, a water channel called aquaporin-4 on astrocytes – an important support cell in the brain – regulates the flow of CSF.

When the team conducted the stroke experiments in mice genetically modified to lack aquaporin-4, CSF flow into the brain slowed significantly.

Aquaporin-4 inhibitors currently under development as a potential treatment for cardiac arrest and other diseases could eventually be candidates to treat stroke.

“Our hope is that this new finding will lead to novel interventions to reduce the severity of ischemic events, as well as other brain injuries to which Soldiers may be exposed,” said Matthew Munson, Ph.D., program manager, fluid dynamics, Army Research Office, an element of the U.S. Army Combat Capabilities Development Command’s Army Research Laboratory.

“What’s equally exciting is that this new finding was not part of the original research proposal. That is the power of basic science research and working across disciplines. Scientists ‘follow their nose’ where the data and their hypotheses lead them – often to important unanticipated applications.”

Additional co-authors of the study include Ting Du, Amanda Sweeney, Guojun Liu, Logan Bashford, Edna Toro, Jeffrey Tithof, Douglas Kelley, John Thomas, Orestes Solis, and Rupal Mehta with University of Rochester, Andrew Sampson, Weiguo Peng, Kristian Mortensen, Frederik Staeger, Peter Bork, Hajime Hirase, and Yuki Mori with the University of Copenhagen, Poul Hjorth and Erik Martens with the Technical University of Denmark, Pablo Blinder with Tel Aviv University, and David Kleinfeld with the University of California, San Diego. The Center for Translational Neuromedicine maintains labs at both URMC and the University of Copenhagen.

Funding: The research was supported with funding from National Institute of Neurological Disorders and Stroke, the National Institute of Aging, the U.S. Army Research Office, Fondation Leducq Transatlantic Networks of Excellence Program, the Novo Nordisk and Lundbeck Foundations, and E.U. Horizon 2020.

Fluid movement within the brain

Fluids and Barriers of the CNS is currently producing a thematic series on this subject, entitled, CNS Fluid and Solute Movement: Physiology, Modeling and Imaging.

Perivascular and parenchymal fluid flow

The concept of a glymphatic system has engendered a surge in interest in fluid (and associated solute) flow within the brain [84].

The proposed glymphatic system involves fluid entry into brain along the arterial perivascular space, fluid movement through brain parenchyma that is astrocyte and aquaporin-4 dependent, and fluid exit from brain along the venous perivascular space.

There is evidence that this system is altered by variables such as exercise [85], circadian rhythm [86] and disease states [84]. However, recently the concept of a glymphatic system has been vigorously debated (for reviews see [8487]).

Most evidence for the glymphatic system comes from studies on perivascular flow using two-photon microscopy and also now with Magnetic Resonance Imaging [8890]. However, it should be noted that even that component has been questioned. For example, Faghih et al. [13] have tried to computer model fluid flow within the glymphatic system and found it implausible based on current anatomical and pressure gradient data.

Another modeling paper, Rey and Sarntinoranont [14], also predicted that fluid flow in the perivascular space would be oscillatory with no net flow over time. Most studies of the glymphatic system are currently based on solute tracking rather than measuring fluid flow and new techniques to examine the latter could be very informative.

The parenchymal component (astrocyte/aquaporin-4 mediated) of the glymphatic system has been the most difficult to study. However, Huber et al. [91] did recently report that an aquaporin-4 facilitator promotes brain interstitial fluid circulation. Recently, a potential alternate link between the periarterial and perivenous spaces has been proposed for fluid and solute flow, a pericapillary space [60].

Anatomically, the vascular basement membrane is secreted by endothelial cells and perivascular cells (pericytes/astrocytes) and a gap between these types of the basement membrane may form the basis of a pericapillary space [59].

Also in contrast to the original glymphatic hypothesis, a recent study by Albargothy et al. [92] concluded that tracers in the CSF pass into the brain parenchyma along the pia-glial basement membrane alongside arteries and exit the brain along intramural pericapillary and periarterial basement membranes.

One proposed role of the glymphatic system is in the clearance of potentially toxic peptides/proteins from the brain, including β-amyloid [84].

The evidence on the relative importance of perivascular drainage of β-amyloid versus BBB transport has recently been reviewed in depth by Hladky and Barrand [44]. They contend that the current evidence favors the BBB as being the most important route.

University of Rochester Medical Center


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