[Neurosciences] The glymphatic system: the brain drainage system?

We are now 3 years after the description of the lymphatic system by Iliff and colleagues (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582150/) and the literature has been growing and its implication in neurological diseases as well. A recent message on my Facebook page (https://www.facebook.com/bbbscientist/) asked my thoughts on that topic and I thought it would be worthwhile to discuss about the glymphatic system since what was a couple of years ago disputable as some in the field considered maybe an artifact (also because it was also obvious how everyone missed that system until now) seems to gain momentum and acceptance.
I thought it would be worth to write down a concise review on the glymphatic system and its implication in some neurological diseases, using the current existing literature.

1. What is the glymphatic system?


In mammalians, plasma (devoid of any blood cells) from blood vessels can diffuse passively into the connective tissue and become what we refers as the interstitial fluid. This interstitial fluid perfuse the tissue between the cells and recovered by a drainage system called the lymphatic system. The lymphatic system is a circulatory system sharing the same origin than arteries and veins, as it is also formed by a endothelium. However such endothelium has a cellular phenotype differing from the endothelium lining the arteries and veins.
The lymphatic system ends up connecting to the thoracic duct that ends up in the vena cava superior and reinject the lymphatic fluid into the blood system. This lymphatic system have two functions: It contributes in a convection flow and the maintenance of the hydrostatic pressure within our internal organs and tissues, secondly it provides a robust monitoring system by the presence of lymph nodes highly enriched in immune system. By constantly checking for antigens from bacteria, virus and other pathogens, the immune system provide a constant protection and setup an alarm system.
Until recently, the brain was considered devoid of such lymphatic system. In place of such lymphatic system, the brain has the ventricular system.

The ventricular system produce an interstitial fluid called the cerebrospinal fluid (CSF) produced by the choroid plexus present in the 4th (IV) ventricle and circulate in the brain parenchyma via the ventricular system. It was considered such CSF was working within a closed system, being reabsorbed by the ependyma layer lining the ventricular system and by the sinus vein (located underneath the choroid plexus) and superficial venous system present on the brain surface.
This was the “textbook” model that was accepted by everyone but yet was filled by biophysical caveats. The study from Rennels and colleagues in 1985 already described the presence of a perivascular system capable to distribute within the whole brain through the injection within the subarachnoid space. The subarachnoid space is a virtual space that is sandwiched between the pia matter (an epithelial layer forming the most internal meaning layer) and the dura matter (the meningial layer lining underneath the skull).
This study was remaining fairly discrete and it was only until  Maiken Nedergaard and colleagues (University of Rochester, NY, USA) study published in JCI in 2013 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582150/pdf/JCI67677.pdf), followed by the publication of Johnathan Kipnis and colleagues (http://www.nature.com/nature/journal/v523/n7560/full/nature14432.html).
The glymphatic system is what we refer as a “paravascular” (distinct from blood vessels) system that provide a conduction system system for the CSF that is external of the ventricular system as illustrated by the following chart from a recent review by  Tarrasoff-Conway and colleagues (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694579/pdf/nihms744165.pdf):
This provide a convection system providing a CSF flow diffusing inside the CNS and clearing out. Note this glymphatic system starts then the pill arteries (red) enters the brain and creates a particular space called the “Virchow-Robin space” and run through medium-size vessels (as these vessels have a smooth muscle layer). This flow occurs in medium to big-size caliber arteries but we don’t know if such system also occurs in brain capillaries, the place of the blood-brain barrier (BBB). Finally, the CSF is drained by veins, allowing the removal of metabolic waste and cellular debris (this point is important for Alzheimers).
If you are more a YouTube enthusiast, there is a video for the glymphatic system:

2. What is the function of the glymphatic system? 

We have still not a complete understanding of the glymphatic system in the CNS, however we can guess its function by looking at neurological diseases.
Firstly, it seems that this glymphatic system plays a role in Alzheimer’s disease (AD).  AD is characterized by the presence of aggregates of amyloid beta inside the brain. Such aggregates (also called oligomers) are capable to induce neuronal cell death. The glymphatic system therefore appears to play a role in the “drainage” of the brain parenchyma. A disturbance of this glymphatic system may result in an indirect accumulation of amyloid-beta peptide, as suggested in a recent study using a mouse model of AD (http://www.ncbi.nlm.nih.gov/pubmed/27234656). This is also supported by another recent study showing an impaired glymphatic system in patients with Type 2 diabetes mellitus (T2DM, the obesity-driven type of diabetes), as T2DM is an important risk factor for AD and other vascular cognitive impairments (also referred as vascular dementia). (http://www.ncbi.nlm.nih.gov/pubmed/27306755).
The importance of the glymphatic system in other neurological diseases, in particular multiple sclerosis (MS) has yet to be demonstrated although some websites associated this system with MS yet without citing literature to support such claims.




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