Cerebrospinal fluid influx drives acute ischemic tissue swelling

H Mestre, T Du, AM Sweeney, G Liu, AJ Samson… - Science, 2020 - science.org
H Mestre, T Du, AM Sweeney, G Liu, AJ Samson, W Peng, KN Mortensen, FF Stæger
Science, 2020science.org
INTRODUCTION Cerebrospinal fluid (CSF) covers and protects the brain from mechanical
injury. CSF also flows along an interconnected network of perivascular spaces surrounding
blood vessels and communicates with interstitial fluid permeating brain tissue, aiding in the
removal of metabolic waste produced by cells. This glial cell–mediated lymphatic
(glymphatic) function of CSF represents a continuous source of fluid and ions for the brain.
When a cerebral artery is occluded, nearby brain tissue is abruptly deprived of blood flow …
INTRODUCTION
Cerebrospinal fluid (CSF) covers and protects the brain from mechanical injury. CSF also flows along an interconnected network of perivascular spaces surrounding blood vessels and communicates with interstitial fluid permeating brain tissue, aiding in the removal of metabolic waste produced by cells. This glial cell–mediated lymphatic (glymphatic) function of CSF represents a continuous source of fluid and ions for the brain. When a cerebral artery is occluded, nearby brain tissue is abruptly deprived of blood flow, oxygen, and glucose. This process, known as acute ischemic stroke, is a leading cause of morbidity and mortality worldwide. After stroke, fluid accumulates in ischemic tissue, and the brain becomes edematous and begins to swell, a dangerous complication of the disease. In the first hours after occlusion, the degree of swelling correlates with the net gain of cations, primarily sodium, and this gain draws in fluid from surrounding sources.
RATIONALE
Because the brain is already encased by CSF, we asked if glymphatic flow could play a role in early edema formation. To test this, we evaluated CSF dynamics using in vivo magnetic resonance (MR) and multimodal optical imaging after occluding the middle cerebral artery in mice. Edema was assessed using diffusion-weighted MR, and edema fluid sources were labeled using radionuclides. Changes in the flow of CSF in perivascular spaces were explored using a network model of the mouse middle cerebral artery. Histology was used to evaluate edema formation in regions adjacent to CSF inflow routes in mouse and human autopsy tissue.
RESULTS
We found that within minutes of ischemic stroke, CSF flowed rapidly into brain tissue along perivascular spaces. Its entry coincided with the onset of swelling and increased brain water content. Radionuclides and multimodal imaging confirmed that CSF was the earliest contributor of both fluid and ions. Calcium imaging in transgenic mice expressing GCaMP7 in cortical neurons and astrocytes revealed that this process was initiated by spreading depolarizations that were triggered when tissue was deprived of blood flow. Diffusion-weighted MR imaging showed that this was the earliest phase of edema formation. This aberrant CSF inflow was found to be caused by spreading ischemia, the pathological constriction of cerebral blood vessels that follows spreading depolarizations. We present a network model that predicts that the space left unoccupied after vessels constrict would be filled by an inrush of CSF that nearly doubles flow speed. That prediction was confirmed experimentally using particle tracking velocimetry of CSF flow in live mice. Inflow depended on the aquaporin-4 water channel that is highly expressed by glial cells (astrocytes), which is a key contributor to glymphatic function. Postmortem examination of rodent and human brains showed increased fluid accumulation in tissue surrounding perivascular spaces and the cerebral ventricles compared with regions deep in the brain that were far from large CSF reservoirs.
CONCLUSION
Here, we demonstrate that CSF can provide a source of ischemic edema. Glymphatic inflow of CSF appears to be the primary initial event driving tissue swelling. This finding challenges our current understanding of edema formation after stroke and may provide a basis for treatment of acute ischemic stroke. Spreading depolarizations continue several days after stroke and are also present in many other neurological conditions, ranging from traumatic brain injury to migraine; therefore, it will be important to determine if spreading edema is also a feature of these diseases and whether CSF …
AAAS