Quantitative Gd‐DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA‐SPGR at 9.4T

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The brain has a high metabolic activity and the parenchyma is devoid of lymph vessels seen in other tissues. The glymphatic system was recently proposed as a substitute for lymphatics to remove the brain's metabolic waste 1. The glymphatic system is defined anatomically by the perivascular compartment and functionally by the aquaporin‐4 water channels of glial end‐feet that ensheathe the vasculature of the central nervous system. The aquaporin‐4 water channels play a pivotal role in regulating cerebrospinal fluid (CSF) flux from the perivascular space into the interstitial fluid (ISF) space 1. The glymphatic pathway is engaged in the removal of metabolic waste including soluble Aβ and tau proteins 1 and is potentially a novel therapeutic target for preventing Alzheimer's disease and other diseases characterized by protein aggregations. Glymphatic transport of waste solutes is a complex process involving periarterial CSF influx, CSF‐ISF exchange, and perivascular CSF‐ISF waste efflux via perivenous conduits with ultimate drainage to lymphatic vessels, including the recently discovered meningeal lymphatic vessel 5. Glymphatic transport is controlled by a wide variety of physical forces such as intracranial pressure gradients [e.g., body posture 6], respiration 7, and cardiac pulsation 8 and, most intriguingly, by the sleep/wake state transition 9.
The discovery and functional characterization of the glymphatic system emanated from studies using in vivo optical imaging techniques. We previously introduced the dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) in combination with the delivery of a small molecular weight paramagnetic contrast agent into the CSF to capture temporal and spatial characteristics of solute transport via the glymphatic pathway 1. Key assumptions for characterizing the glymphatic transport employing DCE‐MRI were 1) that the paramagnetic contrast was treated by the brain as a surrogate extracellular “waste” solute in CSF and ISF and 2) that it was inert with respect to normal brain physiology. Briefly, with DCE‐MRI, the transport of paramagnetic contrast was tracked in the CSF and brain parenchyma over time through a time series of post‐contrast–enhanced images 10. There are several advantages of the DCE‐MRI approach for studying the glymphatic system compared with other known methods. First, DCE‐MRI allows 3D visualization of solute transport in vivo, and therefore provides dynamic visualization of whole brain glymphatic transport, which is not possible with 2‐photon optical imaging. Second, other endogenous MR contrast modalities used in conjunction with DCE‐MRI revealed key anatomical landmarks such as cerebral vasculature, cranial nerves, and sensory organs, which led to the discovery of additional CSF efflux pathways 6. Third, because the DCE‐MRI data deliver spatial and temporal information concurrently it allows more accurate interpretation of the dynamic glymphatic transport process. This is important because multiple coexisting processes are active during the transport and clearance of parenchymal brain waste. Finally, paramagnetic contrast agents are clinically relevant for translational studies of glymphatic transport 11.
The time series of 3D T1‐weighted spoiled gradient echo (SPGR) brain images acquired during and after paramagnetic contrast delivery into the CSF space were previously used to quantify the contrast‐induced “enhancement ratio” (defined by percent signal change from the baseline) as a proxy of the contrast concentration. With this semiquantitative approach, the spatial and temporal characteristics of glymphatic transport revealed an influx of CSF along major arteries and parenchymal uptake 10, allowing characterization of changes in glymphatic transport that might occur in a disease 12 or with altered physiological state 6. Previous studies using other techniques did not derive actual parenchymal or CSF solute fluxes and therefore remain semiquantitative. For example, ex vivo optical or electron microscopy techniques cannot distinguish between slow CSF‐ISF exchange and more rapid clearance rates because they are inherently qualitative and temporally static.

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