Brain-wide pathway for waste clearance captured by contrast-enhanced MRI
Jeffrey J. Iliff, … , Maiken Nedergaard, Helene Benveniste
Jeffrey J. Iliff, … , Maiken Nedergaard, Helene Benveniste
Published March 1, 2013; First published February 22, 2013
Citation Information: J Clin Invest. 2013;123(3):1299-1309. https://doi.org/10.1172/JCI67677.
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Technical Advance

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI

Abstract

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer’s disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer’s disease susceptibility and progression in the live human brain.

Authors

Jeffrey J. Iliff, Hedok Lee, Mei Yu, Tian Feng, Jean Logan, Maiken Nedergaard, Helene Benveniste

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Figure 1

Paravascular influx of paramagnetic contrast.

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Paravascular influx of paramagnetic contrast. (A) 3D visualization of ke...
(A) 3D visualization of key anatomical structures in the rat brain prior to administration of contrast. The anatomical structures include the pituitary (light blue), hippocampus (green), superior colliculus (orange), inferior colliculus (dark blue), pineal gland (yellow), and relevant arterial segments (red). The olfactory artery (OA), azygos of the anterior cerebral artery (azACA), azygos pericallosal artery (AzPA), the middle internal frontal artery (IFA), and the posterior lateral choroidal arterial complex were visualized. (B) A 2-dimensional T1-weighted MRI with the color-coded anatomical structures displayed. (C–E) The time series demonstrates early influx of the small molecular weight paramagnetic contrast agent Gd-DTPA (MW 938 Da). (C) The time at which the intrathecally infused Gd-DTPA appears in the cisterna magna is defined as 0 minutes, and (D and E) the earliest part of the influx process is demonstrated in the subsequent time frames and shows that Gd-DTPA enters the brain along paravascular pathways. (F–H) The dynamic time series of early influx of the large molecular weight paramagnetic contrast agent GadoSpin (MW 200 kDa) also shows that transport into the brain is paravascular. Note that it is evident that even though the 2 paramagnetic contrast agents differ in molecular weight, they pass through paravascular conduits at similar rates, supporting that CSF bulk flow governs this process. (I and J) Paravascular transport of the paramagnetic contrast agent is demonstrated particularly clearly at the level of the Circle of Willis along the internal carotid (IC) artery, posterior communicating (Pcom) arteries, and lateral orbitofrontal artery. Scale bar: 3 mm.