The glymphatic system hypothesis is a concept associated with the dynamics of cerebrospinal fluid and interstitial fluid in the central nervous system. Since this concept was proposed by Iliff et al. and Nedergaard et al. in 2012 (1), it has attracted attention from a wide range of fields and a number of associated reports were published shortly thereafter. This hypothesis does not represent a discovery of a previously unknown anatomical structure. Instead, it appears to be based on a review of an already known structure from the perspective of the function of waste product clearance from the brain. The hypothesis can be roughly summarized as follows: “when the tracer is injected into the cerebrospinal fluid space, it first enters the perivascular space around the arteries. When the tracer is injected directly into the brain tissue, it accumulates in the perivascular space around the veins.” Thus, “cerebrospinal fluid may have a function of clearing the waste products of the brain from the perivascular spaces through the interstitium.” This appears to be a revolutionary hypothesis that treats the interstitial fluid in the brain parenchyma as part of the fluid dynamics, including the cerebrospinal fluid.
Tracer studies are one of the most efficient methods to visualize or evaluate mass transport systems in the living body. The studies by Iliff et al. to build up the glymphatic system hypothesis involved observations of the subcortical region of the mouse brain in vivo by two-photon imaging using a fluorescent tracer and laser-scanning microscope. After the initial publication by Iliff et al., follow-up experiments investigated the glymphatic system hypothesis in MRI studies using intrathecal administration of gadolinium-based contrast agent (GBCA) as a tracer (2,3). In contrast to observations of a fluorescent tracer by laser-scanning microscopy which can only visualize the surface of the brain, MRI is a method that provides tomographic images and evaluation of the whole brain. Evaluation using intrathecally injected GBCA as tracers has also been reported in humans. For example, there was one report of an accident in a clinical setting in which relatively high doses of GBCA were intrathecally injected (4) and other reports show cases in which small doses of GBCA were systematically injected into the intrathecal space for diagnostic purposes (5,6). These reports have shown that GBCA penetrates and flows from the brain surface to the cortex and further deep brain tissues in humans, which confirm that cerebrospinal fluid also flows from the brain surface into the parenchyma in humans, and suggest that GBCA can be used to evaluate the activity of the system. There is a report of intrathecal injection of gadolinium-based contrast media for evaluation of the decreased activity of the glymphatic system in normal pressure hydrocephalus (7). Intravenous injection of GBCA to evaluate the glymphatic system has also been reported. Regarding evaluation of the brain parenchyma, one study evaluated the permeation of intravenously injected GBCA into normal brain tissue using permeability imaging. This study reported that the transfer coefficient for the blood-brain barrier is elevated in patients with Alzheimer’s disease (8). Furthermore, transfer of intravenously injected GBCA into the cerebrospinal fluid has also been confirmed in humans. At approximately 4 hours after intravenous injection of GBCA, transfer of GBCA into the cerebrospinal fluid and Virchow-Robin space at the base of the brain can be observed on heavily T2-weighted fluid-attenuated inversion recovery images (9).

Acknowledgements

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