25th June 2021, Dr Chee L Khoo
The human circulatory system processes about 20 litres of blood per day through capillary filtration. About 17 litres of the filtered plasma is reabsorbed directly into the blood vessels while the remaining three litres are left in the interstitial fluid. One of the main functions of the lymphatic system is to provide an accessory return route to the blood for that surplus three litres as well as clearance of waste products. Clearance of excess fluid and interstitial solutes is critical for tissue homeostasis. Does the brain have a lymphatic system? Recent studies have pointed to the role of the brain’s lymphatic system in the development of neurodegenerative diseases including dementia as well as traumatic brain injury. Where is the brain’s lymphatics?
Although the brain and spinal cord are characterised by a disproportionally high metabolic rate,
and synaptic transmission is exquisitely sensitive to changes in their environment, the brain completely lacks conventional lymphatic vessels. It was always thought that the cerebral spinal fluid (CSF) provides the brain with nutrients, transports catabolites and the blood brain barrier (BBB) keeps nasties (including organisms, misfold-prone proteins out of the brain) and maintains brain homeostasis and regulates the immune function. However, it left many unanswered questions as to how the CSF gets rids of its waste.
Brain vascular flow
The brain is supplied by two carotid and two vertebral arteries which communicate with each other at the anterior and posterior communicating arteries at the Circle of Willis. From the Circle of Willis,
the anterior circulation supplies the evolutionary younger parts of the brain including the neocortex of the cerebral hemispheres while the posterior circulation supplies the brainstem and cerebellum.
Blood from the brain’s interior (parenchyma), including the deep white and gray matter surrounding the lateral and third ventricles flows into the larger central/deeps veins and exits the cerebral cortex and subcortical white matter via the cortical veins that extend to the brain surface as pial veins. The superficial cortical veins anastomose with the deep veins and partly, empty into the superior sagittal sinus and from there into the sigmoid sinus. Thus, blood exits from the brain via both the sinus and jugular veins.
CSF is thought to be produced primarily by the choroid plexuses, which are expansions of the ependymal epithelium, lining the lateral, third, and fourth ventricles. The choroid plexuses are highly folded and vascularised structures consisting of a single layered of cuboidal or low cylindrical epithelium residing on a basement membrane. CSF is continuously produced and is renewed approximately four times each 24 hours. CSF is drained into the peripheral lymphatic system by efflux via the olfactory bulb and along cranial and spinal nerves. From the subarachnoid space, CSF is driven into the Virchow-Robin spaces (see below) by a combination of arterial pulsatility, respiration, slow vasomotion and CSF pressure gradients.
The Glymphatic system
The glial-lymphatic system or glymphatic system is a recently discovered macroscopic waste clearance system that utilises a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system. Besides waste elimination, the glymphatic system also facilitates brain-wide distribution of several compounds, including glucose, lipids, amino acids, growth factors and neuromodulators.
On the surface of the brain, the cerebral arteries extend into pial arteries running through the CSF-containing subarachnoid space and the subpial space. As pial arteries penetrates into the brain parenchyma they transition into penetrating arterioles and create a perivascular space, known as the Virchow-Robin space. CSF in the Virchow-Robin space enters the brain parenchyma along the arterial paravascular space, mixed with interstitial fluid in a process facilitated by aquaporin-4 (AQP4) on the astrocyte webfeet. The CSF/interstitial fluid mix then exits through extracellular space along the venous paravascular space into the cervical lymphatic system. It is thought that paravascular glymphatic pathway driven by AQP4-dependent bulk flow constitutes a major clearance pathway of interstitial fluid solutes from the brain’s parenchyma.
Glymphatic flow in sleep
Glymphatic activity, at least in part, is driven by arterial pulsatility and explains why perivascular influx occurs preferentially around pulsating arteries and not cerebral veins. Any disruption to the arterial pulsatility will affect glymphatic flow with consequences in clearance of solutes. This may explain neurodegenerative diseases in our patients with ischaemic diseases.
Intriguingly, the glymphatic system function mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of activity that enables elimination of potentially neurotoxic waste products, including β-amyloid. In vivo 2-photon imaging of glymphatic function showed that the CSF influx in the awake state was reduced by 90 % compared to anesthetised mice.
Thus, a major function of sleep appears to be that the glymphatic system is turned on and that the brain clears itself of neurotoxic waste products produced during wakefulness. Sleep disturbance (e.g. in sleep apnoea) will affect glymphatic activity with adverse consequences.
In our next issue, we will look at the evidence that demonstrates that glymphatic function is suppressed during aging and in various diseases and how the failure of glymphatic function in turn might contribute to pathology in neurodegenerative disorders, traumatic brain injury and stroke.
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Natale G, Limanaqi F, Busceti CL, Mastroiacovo F, Nicoletti F, Puglisi-Allegra S and Fornai F (2021) Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS. Front. Neurosci. 15:639140. doi: 10.3389/fnins.2021.639140
Lymphatic system – Wikipedia – Accessed on 24th June 2021