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A Novel MRI Phantom to Study Interstitial Fluid Transport in the Glymphatic System
Michal E Komlosh1,2, Dan Benjamini1,2, Nathan H Williamson1, Ferenc Horkay1, Elizabeth B Hutchinson2,3, and Peter J Basser1

1NICHD, NIH, Bethesda, MD, United States, 2CNRM, USUHS, Bethesda, MD, United States, 3NIBIB, NIH, Bethesda, MD, United States

Synopsis

The glymphatic system transports cerebral spinal fluid throughout the brain to clear metabolic and cellular waste during sleep. While there is growing recognition of the critical role this system plays in maintaining normal brain health and in explaining pathology, there are no known noninvasive imaging methods to measure and characterize the efficacy of glymphatic transport in vivo. In this study, we designed, constructed, and tested a glymphatic transport magnetic resonance imaging (MRI) flow phantom. Using it, we determined it may be possible to detect interstitial glymphatic flows via diffusion MRI acquisition methods.

Introduction

The glymphatic system was recently identified1,2 as the primary system for removing toxic waste that accumulates in the parenchyma of the vertebrate brain. The proposed mechanism3-5 is presented in Figure 1a. A glymphatic system that functions poorly—as a result of aging brain 6or traumatic brain injury (TBI)—can lead to severe neurological pathologies7-10. Understanding the glymphatic system’s mechanisms of transport is crucial for understanding the sequelae of TBI and other neurodegenerative diseases. Diffusion-weighted MRI (DW-MRI) methods11-13, which are sensitive to net water displacements, are a prime candidate for detecting features of flow of cerebral spinal fluid (CSF) through the parenchyma. Estimating flow rates through the parenchyma in vivo14 is challenging because the tissue is complex and experimental resolution is insufficient. In this study, we report the design, development, and testing of a novel MRI phantom that possesses salient features of brain parenchyma. We assessed whether diffusion tensor imaging (DTI) could detect, measure, and map interstitial glymphatic flows.

Materials and Methods

The MRI phantom used to model glymphatic flows in this study was prepared as follows: 10-μm diameter (Thermo Scientific) polystyrene microspheres were packed in water in a 5-mm inner diameter Tricon 5/100 Column (GE Healthcare), creating a randomly packed bead pack (representing brain parenchyma) with a water zone above (representing a CSF-filled para-arterial space) (Figure 2). The column was placed inside a Bruker 7T vertical wide-bore magnet with an AVANCE III spectrometer equipped with a micro2.5 microimaging probe. A peristaltic pump (Pharmacia Biotec) circulated water through the bead pack. A mean flow rate close to the reported value for the glymphatic systemflow rate15-19, 0.44 ml/min, was used. The feasibility of detecting glymphatic flow in vivo was tested by using two DWI echo-planar imaging (EPI) acquisition protocols with parameters: TE/TR = 59/3000 ms, axial slices (one for the bulk layer and one for the bead pack) with a spatial resolution = 125 x 125 x 2000 mm3. For the first acquisition, Δ = 50 ms, δ = 3 ms, b = 400, and 800 s/mm2. For the second acquisition, Δ = 25 and 50 ms, δ = 3 ms, and b = 0:100:600 s/mm2 with 21 gradient orientations. ADCs parallel (Dzz) and perpendicular (Dxx) to the flow direction, mean diffusivity (MD), and fractional anisotropy (FA)13 were calculated.

Results and Discussion

Figures 3 and 4 show the FA, Dxx, Dzz, and MD maps for 0 and 0.44 ml/min flow rates, along with the corresponding mean metrics calculated from a circular region of interest (ROI). In the bulk water ROI the DTI parametric maps appear uniform and the calculated FA and MD appear isotropic and homogeneous. The introduction of flow into the bead layer increases the mean values for all DTI metrics. For in vivo experiments, in which the voxel resolution exceeds the parenchyma dimensions, detection of pure coherent flow is highly unlikely. Rather, two scenarios are likely: (1) tissue that is randomly oriented on the voxel scale (mimicked in our phantom system in the transverse direction) or (2) voxels with partial volumes of both coherent (e.g., in a blood vessel) and incoherent flow (in parenchyma). In the latter scenario, FA and MD parameters may be the most suitable candidates for further study. Figure 5 presents a table of the ADC dependence on diffusion time. The table shows that the longitudinal and transverse ADC in the bulk region and Dxx in the bead region do not depend on the observation time, which means that the fluid probes the entire heterogeneous system during the observation period. In the longitudinal direction of the bead layer (Dzz), however, a clear dependence in the observation period appears, which is consistent with results from Khrapitchev and Callaghan20. Their results predict that Dzz in our phantom should reach a steady state for D > 120 ms. Given the spatial resolution of in vivo MRI and the expected tissue microstructure, glymphatic flow would most likely appear as isotropic dispersion, which is mimicked by the transverse flow in the bead region. Our Dxx measurements indicate that the tissue would likely be in a steady state when glymphatic flow is measured by using a typical DTI protocol.

Conclusion

In this study we designed, constructed, and tested a transport MRI phantom to assess the feasibility of detecting glymphatic flow using DWI. The values for the DTI-derived metrics increased significantly during flow as compared with the stationary conditions in the bead layer. This phantom, although oversimplified, indicates that DTI has the potential to detect flow within the range of CSF flow rates in human tissue.

Acknowledgements

This work was supported by funds provided by the Intramural Research Program of the Eunice Kennedy ShriverNational Institute of Child Health and Human Development (grant number ZIAHD000266) and the Center for Neuroscience and Regenerative Medicine (CNRM) under the auspices of the Henry Jackson Foundation (HJF). The authors thank Ms. Liz Salak for editing the manuscript.

References

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Figures

a. Schematic of glymphatic flow through the parenchyma. CSF water from the para-arterial space enters the parenchyma via the Aquaporin-4 (AQP4) water channels, situated on the glial cell end-feet, creating convection flow that drives molecular and other waste toward the para-venous space; from there, the waste eventually drains into the lymphatic system. b. Schematic of water flow through the phantom. The phantom’s bead layer, comprising beads of 10-μm diameter, simplifies the complex nature of the parenchyma. Constant water flow causes convection that simulates the dispersion process that occurs in the glymphatic system.

The MRI flow system consists of a. a peristaltic pump that produces flow though the column, which is placed in the 7T magnet. b. a GE column (magnified here) packed with a layer made of 10-μm beads (parenchyma) and a free-water layer (para-vascular space), also shown are with T2-weighted images from the bead and bulk layers.

DTI FA maps and their mean values for the bulk (a,c) and bead (b,d) layers. a and b: no flow. c and d: flow rate of 0.44 ml/min.

DTI ADC and MD maps and their mean values for the bead (a–f) and bulk (g–l) layers. a–c. and g–i: no flow. d–f and j–l: flow rate of 0.44 ml/min.

ADCs parallel (Z) and perpendicular (X) to the flow direction values of the phantom’s bulk and bead layers at a flow rate of 0.44 ml/min at different observation times.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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