In recent years, mass transport system in the brain by cerebrospinal fluid or interstitial fluid has been clarified from the researches until now. Glymphatic system is the waste clearance pathway system by cerebrospinal fluid through perivascular space and interstitial space in the brain. To visualize or evaluate the waste clearance system of the brain, tracer studies are mostly applied and findings on the system has been accumulated. There are several approaches other than tracer studies to evaluate the dynamics of the interstitial fluid within the brain including diffusion images. Findings from these studies will be discussed in this lecture.
The tracer studies would be the method to evaluate the dynamics of the neurofluids in most cases especially in the animal experiments. The initial study to figure out the glymphatic system by Iliff et al. was an in vivo tracer study using mice. In the study, they used fluorescent tracers injected into the cisterna magna, which were observed by using two-photon microscopy. They observed that cerebrospinal fluid rapidly enters the brain along the cortical pial arteries and followed by influx into the Virchow-Robin spaces along penetrating arterioles. In order to visualize the whole brain dynamics of the neurofluids, MRI was used with the gadolinium based contrast agents (GBCAs) as tracers. Gaberel et al. made minimally invasive injection of a gadolinium chelate within the cisterna magna and observed the dynamics of the neurofluids (2). They successfully found out that SAH and acute ischemic stroke significantly impair the glymphatic system perfusion.
Also for human, there are several studies which tried to evaluate the neurofluids dynamics by tracer studies. Intrathecal injection of GBCA is not generally approved, however, some institute established the evaluation system by tracer studies using GBCAs. Ringstad et al. made MRI studies for idiopathic normal pressure hydrocephalus (iNPH) before and at multiple time points through 24 h after intrathecal injection of GBCA at the lumbar level, and found decreased GBCA clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in iNPH cases (3). Studies by intravenous injection of GBCA for evaluation of the neurofluid dynamics is also made. Naganawa et al. find out that the transfer of GBCA to cerebrospinal fluid can be observed on the strongly T2 weighted FLAIR image after 4 hours from the intravenous injection of GBCA (4).
There are some attempts to evaluate the neurofluid dynamics using diffusion images. Taoka et. al tried to evaluate the activity of human neurofluid dynamics by diffusion based technique named Diffusion Tensor Image Analysis along Perivascular Space (DTI-ALPS) (5). In the study, the diffusivity along the perivascular spaces and projection fibers and association fibers were evaluated to get an index of diffusivity along the perivascular space (ALPS-index) and correlated them with MMSE score in Alzheimer’s disease cases, and found significant positive correlation between diffusivity along perivascular spaces shown as ALPS-index and MMSE score, indicating lesser water diffusivity related to severity of Alzheimer’s disease.
In this presentation, the overview on glymphatic system or neurofluids dynamics will be discussed.
1. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Science translational medicine. 2012;4(147):147ra11.
2. Gaberel T, Gakuba C, Goulay R, et al. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? Stroke. 2014;45(10):3092-6.
3. Ringstad G, Vatnehol SAS, Eide PK. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain : a journal of neurology. 2017;140(10):2691-705.
4. Naganawa S, Nakane T, Kawai H, Taoka T. Gd-based Contrast Enhancement of the Perivascular Spaces in the Basal Ganglia. Magnetic Resonance in Medical Sciences. 2017;16(1):61-5.
5. Taoka T, Masutani Y, Kawai H, et al. Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases. Japanese journal of radiology. 2017;35(4):172-8.