This systematic review showed the current research trends of the glymphatic system. The main concepts of the included studies were observation of contrast-enhancement or CSF flow changes within one or multiple anatomical structures of the glymphatic system. Among the 11 included studies, eight were categorized into the contrast-enhanced MRI group, and three were placed in the non-contrast MRI group. For assessment of the glymphatic system, five studies from the contrast-enhanced MRI group were used to perform a time-point dynamic observation of contrast-enhancement within certain targeted locations and demonstrated peak enhancement time. In contrast, three studies from the non-contrast MRI group carried out TOF-MRA or phase-contrast MR encephalography to demonstrate CSF flow within the glymphatic system. Arterial flow induced glymphatic influx from the CSF space to the brain parenchyma, and venous flow induced glymphatic efflux from the brain parenchyma to the MLV.
The traditional concept of the CNS system holds that this system lacks an anatomically defined lymphatic system to assist in CSF-ISF exchange 1. However, recent studies have suggested the presence of anatomical pathways between the CSF and ISF space, and this CSF-ISF exchange should play a role in clearing ISF solute 4–6 from the CNS. In animal studies 4,7,31,32, researchers have observed the glymphatic system using fluorescent CSF tracers and have shown that CSF tracers entered the brain parenchyma from the CSF space and were cleared through the MLV, then the CSF tracers drained into the deep cervical LN 4,7.
On the other hand, to assess the glymphatic system in a human population, many studies have utilized various MRI techniques to observe glymphatic enhancement and/or glymphatic flow 8–18. Especially, recent studies have demonstrated an association between dysfunction in the glymphatic system and variable neurologic disease including traumatic brain injury, Alzheimer’s disease, and normal pressure hydrocephalus as well as the normal aging 2,19−21. In particular, it has been suggested that the impairment of the glymphatic system may be a potential cause for developing normal pressure hydrocephalus and Alzheimer’s disease 9,17,21. In this regard, acknowledgement of the presence of the glymphatic system is expected to provide a potential therapeutic direction for many neurodegenerative diseases.
However, although the concept of a glymphatic system is a newly emerging and clinically meaningful topic, no systematic review for the MRI-based glymphatic system in a human population has been performed so far. Thus, through this systematic review, we aimed to verify the current state of research on the glymphatic system, to improve the robustness of the methodology, and to lay groundwork for future development of a standard imaging protocol for in vivo study. The main strength of this systematic review is that it is the first to demonstrate the glymphatic system in a human population without prior and present CNS pathology.
To be specific the glymphatic system was described as the function of the ISF exchange in the CNS system, and many previous studies 5–7 have reported that the glymphatic system begins in the CSF space and sequentially flows into the brain parenchyma, MLV, and cervical LN (Supplementary Fig. 1A and B). Studies in the contrast-enhanced MRI group revealed peak enhancement time first in the CSF space, followed by the brain parenchyma and MLV, and finally in the cervical LN. This peak enhancement pattern was similar to those of previous studies of glymphatic system flow patterns revealed by the animal radiotracer examinations 6,7, which can verify the demonstration of the glymphatic system presence on the MRI. Moreover, the results of the non-contrast MRI group revealed similar CSF flow patterns in the glymphatic system. They demonstrated that arterial pulsation induces centrifugal flow in the CSF space, while venous pulsation induces centripetal flow in the MLV. In addition, the MLV has countercurrent flow to venous flow. Similar to the change in peak enhancement time on contrast-enhanced MRI, flow change began in the CSF space and extended toward the brain parenchyma and MVL on non-contrast MRI. Therefore, these results can also support the presence of glymphatic pathway in a human population. This verification of the glymphatic flow on contrast-enhanced and non-contrast MRIs could have significant clinical value, because it can be applied to the detection of the glymphatic dysfunction which may reveal the underlying pathophysiology of several neuro-degenerative diseases including Alzheimer disease, normal pressure hydrocephalus, etc. Therefore, we believe that this systematic review could provide the basis for the future studies linking glymphatic function and cerebral degenerative disease.
Based on the relevant studies, we should give the method using contrast-agent superiority over the non-contrast flow-sensitive MRI for the glymphatic imaging, since assessing CSF flow change on non-contrast MRI is a subjective analysis, while contrast-enhanced MRI can not only provide subjective analysis but also objective measurement for the degree of the glymphatic flow changes. Therefore, we highly recommend contrast-enhanced T1-weighted MRI using gadolinium-based contrast-agent for the glymphatic dedicated imaging. With regard to the intrathecal injection of the contrast-agent, we recommend the following time schedule for measuring peak enhancement within the glymphatic system; CSF within 4 ~ 6 hours, parenchyma and MLV within 15 ~ 48 hours, and cervical lymph node more than 24 hours. However, as for the intravenous contrast-agent injection, we could not specifically recommend optimal target structure or time schedule, because there was only one study using intravenous contrast-agent injection. Considering that intravenous contrast-agent injection is much accessible than intrathecal injection in clinical practice, future studies using intravenous injection are warranted to widen its usage to the normal population, and thus to make standard glymphatic imaging protocol and the suitable time schedule for intravenous approach.
Our study had several limitations. First, we included only a small number of studies that investigated study participants without underlying CNS pathology. However, when considering the intrathecal contrast injection is seldomly performed on the selective patients with CSF leakage due to the risk of chemical meningitis and neurotoxicity 33–36, it was inevitable to include a small number of subjects. Second, we included only one study that performed intravenous contrast injection to assess the glymphatic system. This study evaluated contrast enhancement observation at a single time and location. Therefore, it is difficult to draw conclusions about glymphatic flow timing and pattern in studies that used intravenous contrast injection. However, since intravenous contrast injection is safer than intrathecal injection 34,35, future large studies using intravenous injection will contribute to the ever-growing body of glymphatic research. Third, although we made effort to enroll studies that demonstrate glymphatic system within normal healthy population without having significant CNS disorder, studies that performed intrathecal injection included patients who were suspected to have CSF leakage. However, although these patients may not seem as normal healthy population technically, they did not have underlying CNS disease, and their CSF leakage was induced by minor trauma; therefore, we decided to include these patients in our systemic review. Similarly, we included patients with endolymphatic hydrops which is a peripheral vestibular disease, but those without any underlying CNS disease. Therefore, we believe that we could successfully enroll patients without CNS disorders close to normal healthy population. Therefore, we enrolled studies included patients with suspicious CSF leakage or endolymphatic hydrops.
The present systematic review showed imaging sequence, imaging protocol including contrast-agent injection protocol and acquisition time-points on dynamic contrast-enhanced scanning, and the targeted anatomical structures for measuring glymphatic system. Our findings could enhance the understanding of the human glymphatic system and the current MRI protocols for measuring glymphatic flow. Based on the review, we recommend contrast-enhanced T1-weighted MRI over non-contrast flow-sensitive MRI for the glymphatic imaging We believe that future studies linking cerebral degenerative disease and glymphatic functioning can be built on the basis of our current study.