Abstract
The study of brain clearance mechanisms is an active area of research. While we know that the cerebrospinal fluid (CSF) plays a central role in one of the main existing clearance pathways, the exact processes for the secretion of CSF and the removal of waste products from tissue are under debate. CSF is thought to be created by the exchange of water and ions from the blood, which is believed to mainly occur in the choroid plexus. This exchange has not been thoroughly studied in vivo.We propose a modified arterial spin labeling (ASL) MRI sequence and image analysis to track blood water as it is transported to the CSF, and to characterize its exchange from blood to CSF. We acquired six pseudo-continuous ASL sequences with varying labeling duration (LD) and post-labeling delay (PLD) and a segmented 3D-GRASE readout with a long echo train (8 echo times (TE)) which allowed separation of the very long-T2 CSF signal. ASL signal was observed at long TEs (793 ms and higher), indicating presence of labeled water transported from blood to CSF. This signal appeared both in the CSF proximal to the choroid plexus and in the subarachnoid space surrounding the cortex. ASL signal was separated into its blood, gray matter and CSF components by fitting a triexponential function with T2s taken from literature. A two-compartment dynamic model was introduced to describe the exchange of water through time and TE. From this, a water exchange time from the blood to the CSF (Tbl->CSF) was mapped, with an order of magnitude of approximately 60 s.
Highlights
Brain waste clearance mechanisms are still poorly understood, standing in stark contrast to our much deeper general understanding of brain metabolism and function
The first echo time is consistent with more typical arterial spin labeling (ASL) measurements: the signal is seen transitioning from the large arteries in the early time points to perfusing into the tissue and decaying at long post-labeling delay (PLD)
Starting at PLD = 1.5 s, this longT2 signal begins to appear, increasing and peaking around PLD = 2.5 s. This signal is not confined to the choroid plexus, nor does it appear to originate from there, as might be expected based on the current consensus hypothesis of cerebrospinal fluid (CSF) circulation (Milhorat, 1975); the CSF-ASL signal is fairly well distributed around the cortex
Summary
Brain waste clearance mechanisms are still poorly understood, standing in stark contrast to our much deeper general understanding of brain metabolism and function. The interaction of cerebrospinal fluid (CSF) and interstitial fluid (ISF) is thought to form a key aspect of clearance; the exact circulating pathways of these fluids, and the driving forces for motion in and out of tissue, are still under debate This field of study, sometimes referred to as “glymphatics” after one of the hypothesized pathways for these processes (Iliff et al, 2012), has garnered much attention and excitement in recent years as our understanding of brain clearance (Albargothy et al, 2018; Liu et al, 2020; Mestre et al, 2018; Mestre et al, 2020; Wardlaw et al, 2020; Xie et al, 2013; Fultz et al, 2019; van Veluw et al, 2020; Nedergaard and Goldman, 2020; Tarasoff-Conway et al, 2015) has begun to improve. It is essential to move towards human, in vivo experiments, to build upon current knowledge which has come predominantly from rodent experiments, without direct replication in humans
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