The glymphatic pathway has only recently been described and functionally represents the brain’s lymphatic system, although no anatomical structure equivalent to the peripheral lymphatic system is present within the brain parenchyma. It is believed to be a crucial normal homeostatic feature allowing the brain to maintain a stable extracellular milieu, by creating a pathway for the clearance of interstitial fluid and solutes.
The glymphatic pathway comprises three parts which are linked in series 1:
- para-arterial cerebrospinal fluid (CSF) influx route
- transparenchymal pathway
- paravenous CSF interstitial fluid clearance route
Recently, endothelial-lined channels with many of the molecular features of lymphatic channels have been discovered lining the dural venous sinuses 7.
Para-arterial CSF influx route
A large proportion of (40%) CSF readily enters the brain parenchyma via the Virchow-Robin spaces which surround perforating arteries. Propulsion is thought to largely rely on arterial pulsation. Although present essentially surrounding all penetrating arteries, prominent influx nodes have been identified in the pituitary and pineal gland recesses (at least in rats) 1,2.
CSF then proceeds along the arterial vascular smooth muscle basement membrane and then to the capillary bed basal lamina, and from here into the interstitial compartment of the brain parenchyma 1.
However, the CSF to interstitial space exchange appears limited to small molecular weight compounds, with larger compounds remaining ‘trapped’ in the perivascular spaces, not able to enter the interstitial space 2,3.
Bulk flow of interstitial fluid passes through the brain parenchyma from the penetrating arteries to the draining veins.
Paravenous CSF interstitial fluid clearance route
Drainage of fluid into veins relies on the astroglial aquaporin-4 (AQP4) water transport system which is expressed in high concentration on astrocytic end foot processes, co-localized with the rectifying potassium channel and excitatory amino acid transporter (EAAT) 4. The combination of these channels drives interstitial fluid into veins.
Dysfunction of the glymphatic system may be an important contributing feature in a variety of disease states 1. Increasing evidence is emerging that the glymphatic system is important in the normal evacuation of various compounds which otherwise accumulate in the extracellular space, including beta amyloid, suggesting a contributory (or perhaps even fundamental) role in the development of tauopathies 1-3.
Interestingly, there is increased glymphatic flow during sleep 5.
Decreased clearance of soluble amyloid beta, resulting in extracellular deposition of amyloid peptides may be an important factor in the development of Alzheimer disease 1-3. Such a decrease has been seen in older brains due to changes in the distribution and expression of aquaporin-4 and the ease with which CSF enters the interstitium along penetrating arteries 6.
Traumatic brain injury and ischemia
Chronic traumatic encephalopathy is seen in the setting of repeated relatively low energy impacts, such as those experienced in many contact sports (e.g. boxing, American football). A reactive astrogliosis can be identified, with associated changes in AQP4 expression 1. These changes are typically an increase in AQP4 expression during the first few weeks following injury with longer lasting loss of polarity, thought to result in impaired bulk transport of fluid from the interstitial space to the paravenous CSF pathway 1. This in turn is believed to result in impaired clearance of interstitial solutes, including amyloid beta 1.