Science 13Mar2020

SCIENCE sciencemag.org 13 MARCH 2020 • VOL 367 ISSUE 6483 1195

GRAPHIC: V. ALTOUNIAN/

SCIENCE

By Jonathan Moss and Anna Williams

C

erebral edema, brain swelling due

to fluid influx, exacerbates the ef-

fects of ischemic large-vessel stroke,

whereby a clot blocks one of the

large blood vessels to the brain. Be-

cause the skull is a closed box, brain

swelling cannot be accommodated, damag-

ing other areas of the brain and leading

to poor long-term prognoses ( 1 ). The cen-

tral dogma to this fluid influx is that its

source is the blood. On page 1211 of this

issue, Mestre et al. ( 2 ) present compel-

ling evidence to suggest that the initial

stages of cerebral edema after ischemic

stroke are driven by influx from an alterna-

tive source—the cerebrospinal fluid (CSF).

This implies that targeting CSF-driven

edema may offer opportunities to treat

these harmful secondary effects of isch-

emic stroke.

A system was previously described

whereby CSF enters the brain parenchyma

through the spaces around arteries and

leaves through the spaces around veins

(perivascular spaces ), removing brain sol-

utes ( 3 ). This lymphatic-like mechanism is

largely dependent on water flow through

aquaporin-4 (AQP4) channels into, and out

of, the endfeet processes of perivascular as-

trocytic glial cells and was thus called the

glymphatic system. The clearing of brain

solutes by this system can be highly ben-

eficial. Removal of amyloid b peptide and

tau protein can reduce pathological aggre-

gations that are implicated in neurodegen-

eration, Alzheimer’s disease, and dementia.

Indeed, when the glymphatic system is ar-

tificially perturbed by the deletion of the

Aqp4 gene in mice, clearance of these fac-

tors is suppressed and pathology worsens

( 3 , 4 ). But what if this clearance pathway

is overwhelmed? Mestre et al. reveal that,

in the immediate response to ischemic

stroke, perivascular spaces are flooded with

CSF, the physiological ebb and flow of the

glymphatic system are perturbed, and fluid

rushes through AQP4 channels of astrocyte

endfeet into the astrocytes and the brain to

cause edema.

The development of cerebral edema is

typically subdivided into three distinct

phases. First, in cytotoxic edema, brain cells

take on fluid and swell as energy-dependent

ion transport fails. Next, in ionic edema, so-

dium ions from the blood cross an intact

blood-brain barrier and create a permissive

osmotic gradient down which fluid flows

into the brain. Finally, in vasogenic edema,

the blood-brain barrier begins to break, al-

lowing an influx of larger blood constitu-

ents. Using a well-characterized mouse

model of unilateral ischemic stroke (affect-

ing part of one brain hemisphere), Mestre

et al. show that influx waves of water, at

11 s and at 5.5 min after stroke (within the

window of cytotoxic edema), increased

water content in the stroke-affected cor-

tex, and this water remained for an hour.

With a fluorescent CSF tracer, the authors

demonstrate that CSF enters the poststroke

hemisphere three times more readily than

the unaffected hemisphere. Tracers in the

blood or CSF (see the photo) confirmed

that the CSF is the source of the increased

water content, which is corroborated by

edema formation along CSF flow pathways

in humans.

What drives this influx of CSF into the

brain? Mestre et al. found that a poststroke

reduction in blood flow led to a hydrostatic

pressure gradient to push CSF into the brain

at 11 s after stroke. The larger influx of CSF

occurred contemporaneously with cyto-

toxic edema, as seen by a decreased mobil-

ity of water molecules due to cell swelling.

This decrease in mobility may be driven by

spreading depolarizations—sudden waves

of extensive gray matter depolarization re-

sulting from the shutdown of transmem-

brane ion gradients in neurons ( 5 ). The au-

thors found that the wave of depolarization

spreads fast, with the wave of CSF influx

following ~30 s behind, suggesting that the

depolarization triggers CSF influx.

NEUROPHYSIOLOGY

Opening the floodgates to the brain

Cerebrospinal fluid influx dictates early edema in response to ischemic large-vessel stroke

Medical Research Council Centre for Regenerative

Medicine, University of Edinburgh, 5 Little France Drive,

Edinburgh EH16 4UU, UK. Email: [email protected]

Prestroke

Blood-brain barrier intact

Cytotoxic edema

Early stage of edema

with brain tissue swelling

Vasogenic edema

Late stage of edema with

disrupted blood-brain barrier

Water from CSF

Water from blood

PVS Arteries

Wave of spreading

depolarization

Capillary

Astrocyte

endfoot

Mouse

brain

Mous

n

Mous

n

Mous

n

Unafected

hemisphere

Afected

hemisphere

Swelling due

to edema

di

Aquaporin-4

Brain

paranchyma

PVS

Water

Increased

PVS Vasoconstriction

Fluid influx in poststroke edema

In a mouse model of ischemic stroke, a wave of spreading depolarization

leads to waves of vasoconstriction, perivascular space (PVS) enlargement,

and an influx of water from cerebrospinal fluid (CSF) into the brain

through aquaporin-4 expressed on astroctye endfeet, causing early

poststroke edema. This occurs before contributions from

the blood, which exacerbate the edema.

Published by AAAS