Glymphatic pathway

Last revised by Frank Gaillard on 22 Aug 2021

The glymphatic pathway 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 likely to be an important homeostatic mechanism allowing the brain to maintain a stable extracellular milieu, by creating a pathway for the clearance of interstitial fluid and solutes.

Despite years of study, its exact function and importance remain controversial with many fundamental questions remaining unanswered 8

Gross anatomy

The glymphatic pathway comprises three parts which are linked in series 1,8:

  1. periarterial cerebrospinal fluid (CSF) influx route
  2. transparenchymal pathway
  3. perivenous CSF interstitial fluid clearance route into lymphatics and/or veins
Periarterial CSF influx route

A significant proportion of CSF (perhaps as high as 40%) enters the brain parenchyma via the perivascular Virchow-Robin spaces which surround perforating arteries. Propulsion is thought to largely rely on arterial wall pulsatility.

CSF 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.

Transparenchymal pathway

Bulk flow of interstitial fluid passes through the brain parenchyma from the penetrating arteries to the draining veins.

Paravenous interstitial fluid clearance route 

Drainage of fluid into perivenular space 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. From here the eventual drainage of fluid remains uncertain. Possibilities include admixing into the subarachnoid CSF, resorption into venous blood via arachnoid granulations and vili and/or drainage into meningeal lymphatics, particularly well developed at the base of the skull and surrounding the dural venous sinuses 7,8

Related pathology

Dysfunction of the glymphatic system may be an important contributing feature in a variety of disease states 1,8. Increasing evidence, although by no means universally accepted, is emerging that the glymphatic system is important in the normal evacuation of various compounds which otherwise accumulate in the extracellular space, including amyloid-beta and tau, suggesting a contributory (or perhaps even fundamental) role in the development of cerebral amyloid deposition diseases and tauopathies 1-3,8.

Interestingly, there is a diurnal variation in the amount of amyloid-beta and tau identified in the interstitial fluid and CSF. This is believed to be most likely due to increased glymphatic flow during sleep and raises questions about the relationship between healthy sleep habits and the development of neurodegenerative diseases 5,8

Alzheimer disease

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.

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