10th July 2021, Dr Chee L Khoo
In medical school, we were taught that the cerebral spinal fluid (CSF) provides the brain with nutrients, transports catabolites and the blood brain barrier (BBB) keeps nasties out and maintains a stable environment (homeostasis). Now, keeping nasties out is great but how does the brain get rid of the waste it generates?In the last fortnight, we explored how the brain cleans itself of toxic and waste products. Interestingly, most of the work of “cleaning” occurs when we are asleep. Naturally, anything that affects the integrity of the glymphatic system can lead to degenerative diseases. This week, we shall look at what can go wrong and what happens when it does.
At the 2001 Stroke Progress Review Group Meeting of the National Institute of Neurological Disorders and Stroke, the concept of the neurovascular unit (NVU) was formalised to emphasise the relationship between the CNS and its supplying blood vessels. The NVU consist of the vascular endothelial cells (ECs), basement membrane, (BM), perivascular astrocytes, neurons, pericytes and microglia abutting the brain parenchyma. The ECs represent the major BBB with their tight and adherent junctions between adjacent cells which prevent paracellular diffusion of blood solutes while providing structural support for the NVU. Endothelial membrane transporters allow for both influx and efflux of either potentially beneficial or harmful substances across the BBB.
Surrounding neurons are particularly sensitive to changes of blood oxygen and nutrients. They act as metabolic pacemakers. Microglia and phagocytes in the extracellular matrix surrounding blood vessels play a waste clearing and immunological role.
Interstitial fluid and solutes from the brain parenchyma enter the peri-arterial space in the BM of capillaries and within the tunica media of penetrating arteries. From the peri-arterial space, solutes are cleared from the brain by dispersing into the CSF or draining directly into cervical lymph nodes. The presence of lymphatic vessels was demonstrated in the dura of both humans and non-human primates (1-3). In humans, these vessels were detected at the level of the superior sagittal sinus and falx cerebri.
Several lines of evidence documented that β-amyloid and tau exit the brain via the glymphatic system. Glymphatic activity and CSF outflow is significantly decreased in old mice. In animal models, it was observed that during natural sleep or anaesthesia there is an enlargement of the interstitial space, which increases convective CSF exchange with ISF, and β -amyloid clearance rate (4).
Sleep deprivation is correlated with increased levels of β-amyloid in the brain of both animals and humans (5-6). The concentration of β-amyloid in CSF follows the sleep-wake cycle in AD human subjects, providing a correlation between bad sleep quality and β-amyloid deposition in the preclinical stage of AD (7). Obstructive sleep apnoea is associated with cerebral β-amyloid aggregation. Disrupting the brain slow wave activity is enough to abolish waste clearance (8). In patients with Alzheimer’s dementia (AD), a decrease in both BBB and glymphatic function, accompanies a general dysfunction of NVU, including astrocytic end-feet atrophy, pericyte degeneration, alteration of endothelial tight junctions, and thickening of the basement membrane. CSF clearance of β-amyloid and tau tracers is reduced in these patients.
In haemorrhagic stroke, the glymphatic system drainage is impaired from occlusion of the perivascular spaces by fibrin and fibrinogen deposits. In ischaemic strokes, there is impaired CSF inflow and the release of several pro-inflammatory cytokines. Clearance of solutes, including tau protein, from the interstitial space is reduced by > 60% after traumatic brain injury in experimental animals, with this impairment persisting for at least 1 month (10).
Cerebral arterial pulsation plays a pivotal role in driving glymphatic CSF influx into and through the brain parenchyma (9). Thus, loss of arterial pulsatility may contribute to the accumulation of toxic solutes, including β-amyloid, in the aging or ischaemic brain.
In a rat model of chronic liver disease, altered glymphatic clearance occurs in several brain regions. These effects are aligned with cognitive/behavioural deficits. It has been speculated that, in the
advanced phases of liver cirrhosis, glymphatic damage could be the end-stage phenomenon of a cascade of hydrodynamic events. Diabetes mellitus impairs glymphatic clearance of interstitial solutes within the hippocampus and hypothalamus of rats which is correlated with cognitive decline (11).
The glymphatic-cervical lymphatic system – the bi-directional relationship
The glymphatic pathway is connected to a classic lymphatic network, associated with dural meninges covering the brain, as well as sheaths of cranial nerves and blood vessels, or drains via the olfactory route, then exiting through cranial foramina. This network ultimately drains to deep and superficial cervical lymph nodes. Impaired efficiency of meningeal lymphatic vessels to drain toward peripheral lymph nodes play a significant role in the pathological accumulation of proteins implicated in neurodegeneration (Hershenhouse et al., 2019). In a model of transient middle cerebral artery occlusion-induced stroke, the blockade of cervical lymphatics worsened cerebral oedema and infarct size.
While assisting in the drainage of CSF components, meningeal lymphatics enable immune cells and self-antigen peptides to enter draining lymph nodes This may foster activation of T-cells in periphery while mounting CNS-directed adaptive immune responses resection of either meningeal lymphatics or deep cervical lymph nodes is beneficial in models of multiple sclerosis.
It is clear that if CSF does not flow efficiently, it stagnates and accumulates in the perivascular spaces. Minor changes in CSF pressure, tissue pressure, or vascular function may alter the shape of perivascular spaces, leading to an altered flow dynamic in perivascular spaces and secondary flow impairment. its chronic failure may lead to dysregulation of brain waste molecule clearance, intra-extracellular water, ion homeostasis, and CNS immune response alterations. Thus, rather than considering and treating individual neurodegenerative disorders, it might be time to consider all of them under the umbrella of cerebral hydrodynamic disturbances.
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- Absinta, M., Ha, S. K., Nair, G., Sati, P., Luciano, N. J., Palisoc, M., et al. (2017). Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife 6:e29738. doi: 10.7554/eLife.29738
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