Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension

Humberto Mestre,John H Thomas,Amanda M Sweeney,Douglas H Kelley,Wei Song,Jeffrey Tithof,Ting Du,Weiguo Peng,Maiken Nedergaard,Genaro Olveda

doi:10.1038/s41467-018-07318-3

Abstract

Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain is important for clearance of metabolic waste. Arterial pulsations are thought to drive flow, but this has never been quantitatively shown. We used particle tracking to quantify CSF flow velocities in PVSs of live mice. CSF flow is pulsatile and driven primarily by the cardiac cycle. The speed of the arterial wall matches that of the CSF, suggesting arterial wall motion is the principal driving mechanism, via a process known as perivascular pumping. Increasing blood pressure leaves the artery diameter unchanged but changes the pulsations of the arterial wall, increasing backflow and thereby reducing net flow in the PVS. Perfusion-fixation alters the normal flow direction and causes a 10-fold reduction in PVS size. We conclude that particle tracking velocimetry enables the study of CSF flow in unprecedented detail and that studying the PVS in vivo avoids fixation artifacts.

Highlights

Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain is important for clearance of metabolic waste
Recent in vivo experiments in rodents have shown the opposite: CSF enters the brain along arterial PVSs, and this flow plays a vital role in driving the clearance of amyloid-β (Aβ) from the interstitial fluid (ISF) at more downstream locations[1]
Microspheres appeared in the PVSs of the cortical branches of the middle cerebral artery (MCA) an average of 292 ± 26 s after the infusion began; these PVSs are known to be primary influx routes for CSF into the brain[22,23,24]

Summary

Introduction

Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain is important for clearance of metabolic waste. Recent in vivo experiments in rodents have shown the opposite: CSF enters the brain along arterial PVSs, and this flow plays a vital role in driving the clearance of amyloid-β (Aβ) from the ISF at more downstream locations[1]. In both cases, indirect experimental evidence suggests that fluid within PVSs is transported via bulk flow[5,6,7] and possibly driven by arterial pulsations derived from the cardiac cycle[8,9,10,11]. We speculate that hypertension-induced reduction of PVS fluid transport contributes directly to the associations between arterial hypertension and Alzheimer’s disease

Methods

Results

Conclusion