Neurofluid Dynamics and the Glymphatic System: A Neuroimaging Perspective

Abstract

The glymphatic system hypothesis is a concept describing the clearance of waste products from the brain. The term "glymphatic system" combines the glial and lymphatic systems and is typically described as follows. The perivascular space functions as a conduit that drains cerebrospinal fluid (CSF) into the brain parenchyma. CSF guided to the perivascular space around the arteries enters the interstitium of brain tissue via aquaporin-4 water channels to clear waste proteins into the perivascular space around the veins before being drained from the brain. In this review, we introduce the glymphatic system hypothesis and its association with fluid dynamics, sleep, and disease. We also discuss imaging methods to evaluate the glymphatic system.

Keywords: Cerebrospinal fluid; Contrast media; Glymphatic system; Interstitial fluid; Magnetic resonance imaging, Diffusion imaging.

Fig. 1. Overview of glymphatic system and neurofluid concept.

A. Illustrates original concept of glymphatic system. CSF flows into brain parenchyma through periarterial space and enters interstitial space of brain tissue through AQP4-controlled water channels distributed at endfeet of astrocytes that comprise outer wall of perivascular space. CSF entering interstitial space removes waste proteins from tissue. CSF then flows into space around veins and is excreted outside brain. B. Illustrates concept of neurofluids in brain tissue. Interstitial space or CSF space of brain tissue is considered common space that functions not only as support structure but also as space for mass transport, immune function, and/or intercellular signaling. Common space is filled with neurofluids. Neurofluid is term that refers to any type of fluid that fills central nervous system, such as CSF, ISF, and blood. There is exchange between neurofluid compartments. Adapted from Taoka et al. J Magn Reson Imaging 2020;51:11–24 (4). AQP4 = aquaporin-4, CSF = cerebrospinal fluid, ISF = interstitial fluid

Fig. 2. MRI methods for evaluating glymphatic system/neurofluid dynamics.

Several MRI methods have been reported for evaluation of neurofluid (blood, CSF, and ISF) dynamics. Although methods for evaluating blood or CSF dynamics are established, those for evaluating ISF dynamics are under development. Numbers indicate representative references. ASL = arterial spin labeling, DCE = dynamic contrast-enhance, DSC = dynamic susceptibility contrast, GBCA = gadolinium-based contrast agent, IVIM = intravoxel incoherent motion, SLIP = spatial labeling inversion pulse, 4D = four-dimensional

Fig. 3. DTI-ALPS.

Diffusion capacity along the x-, y-, and z-directions measured in each region of interest in projection (blue), association (green), and subcortical (red) areas in radiate crown (A, B). In projection (C) and association (D) areas, diffusion capacity along projection (z-direction: blue) and association (y-direction: green) fibers is inversely correlated with MMSE score. Diffusion capacity in running direction of perivascular space (x-direction: red) is correlated with MMSE score. In other words, with more severe Alzheimer's disease, diffusion capacity tends to decrease. In subcortical area (E), diffusion capacity is inversely correlated with MMSE score in all directions of perivascular space and white matter fibers. We evaluated diffusion capacity along perivascular space using ratio of diffusion capacity along perivascular space, to that in direction perpendicular to running direction of main white matter fibers (ALPS index). ALPS index = mean (Dxproj, Dxassoc) / mean (Dyproj, Dzassoc). ALPS index is significantly inversely correlated with MMSE score (F) and significantly correlated with age (G), suggesting that ALPS index might be indicator reflecting glymphatic system function. Adapted from Taoka et al. Jpn J Radiol 2017;35:172–178, with permission of Japan Radiological Society (41). ADC = apparent diffusion coefficient, DTI-ALPS = diffusion tensor image analysis along the perivascular space, MMSE = Mini-Mental State Examination