Glymphatic system

A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Using a combination of diffusion iontophoresis techniques pioneered by Nicholson and colleagues, in vivo 2-photon imaging, and electroencephalography to confirm the wake and sleep states, Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta.[16] On the basis of these findings, they hypothesized that the restorative properties of sleep may be linked to increased glymphatic clearance of metabolic waste products produced by neural activity in the awake brain.

Another key function of the glymphatic system was documented by Thrane et al., who, in 2013, demonstrated that the brain's system of paravascular pathways plays an important role in transporting small lipophilic molecules.[17] Led by M. Nedergaard, Thrane and colleagues also showed that the paravascular transport of lipids through the glymphatic pathway activated glial calcium signalling and that the depressurization of the cranial cavity, and thus impairment of the glymphatic circulation, led to unselective lipid diffusion, intracellular lipid accumulation, and pathological signalling among astrocytes. Although further experiments are needed to parse out the physiological significance of the connection between the glymphatic circulation, calcium signalling, and paravascular lipid transport in the brain, the findings point to the adoption of a function in the CNS similar to the capacity of the intestinal lymph vessels (lacteals) to carry lipids to the liver.

Although the first known observations of the CSF date back to Hippocrates (460–375 BCE) and later, to Galen (130–200 CE), its discovery is credited to Emanuel Swedenborg (1688–1772 CE), who, being a devoutly religious man, identified the CSF during his search for the seat of the soul.[22] The 16 centuries of anatomists who came after Hippocrates and Galen may have missed identifying the CSF due to the prevailing autopsy technique of the time, which included severing the head and draining the blood before dissecting the brain.[22] Although Swedenborg's work (in translation) was not published until 1887 due to his lack of medical credentials, he also may have made the first connection between the CSF and the lymphatic system. His description of the CSF was of a "spirituous lymph".[22]

In the peripheral organs, the lymphatic system performs important immune functions and runs parallel to the blood circulatory system to provide a secondary circulation that transports excess interstitial fluid, proteins, and metabolic waste products from the systemic tissues back into the blood. The efficient removal of soluble proteins from the interstitial fluid is critical to the regulation of both colloidal osmotic pressure and homeostatic regulation of the fluid volume of the body. The importance of lymphatic flow is especially evident when the lymphatic system becomes obstructed. In lymphatic associated diseases, such as elephantiasis (where parasites occupying the lymphatic vessels block the flow of lymph), the impact of such an obstruction may be dramatic. The resulting chronic edema is due to the breakdown of lymphatic clearance and the accumulation of interstitial solutes.

In 2015, the presence of a meningeal lymphatic system was first identified.[5][6] Downstream of the glymphatic system's waste clearance from the ISF to the CSF, the meningeal lymphatic system drains fluid from the glymphatic system to the meningeal compartment and deep cervical lymph nodes. The meningeal lymphatics also carry immune cells. The extent to which these cells may interact directly with the brain or glymphatic system, is unknown.

For more than a century the prevailing hypothesis was that the flow of cerebrospinal fluid (CSF), which surrounds, but does not come in direct contact with the parenchyma of the CNS, could replace peripheral lymphatic functions and play an important role in the clearance of extracellular solutes.[23] The majority of the CSF is formed in the choroid plexus and flows through the brain along a distinct pathway: moving through the cerebral ventricular system, into the subarachnoid space surrounding the brain, then draining into the systemic blood column via arachnoid granulations of the dural sinuses or to peripheral lymphatics along cranial nerve sheathes.[24][25] Many researchers have suggested that the CSF compartment constitutes a sink for interstitial solute and fluid clearance from the brain parenchyma. However, the distances between the interstitial fluid and the CSF in the ventricles and subarachnoid space are too great for the efficient removal of interstitial macromolecules and wastes by simple diffusion alone. Helen Cserr at Brown University calculated that mean diffusion times for large molecules, such as albumin, would exceed 100 hours to traverse 1 cm of brain tissue,[26] a rate that is not compatible with the intense metabolic demands of brain tissue. Additionally, a clearance system based on simple diffusion would lack the sensitivity to respond rapidly to deviations from homeostatic conditions.

Key determinants of diffusion through the brain interstitial spaces are the dimensions and composition of the extracellular compartment. In a series of elegantly designed experiments in the 1980s and 1990s, C. Nicholson and colleagues from New York University explored the microenvironment of the extracellular space using ion-selective micropipettes and ionophoretic point sources. Using these techniques Nicholson showed that solute and water movement through the brain parenchyma slows as the extracellular volume fraction decreases and becomes more tortuous.[27]

As an alternative explanation to diffusion, Cserr and colleagues proposed that convective bulk flow of interstitial fluid from the brain parenchyma to the CSF was responsible for efficient waste clearance.[26]

Experiments conducted at the University of Maryland in the 1980s by Patricia Grady and colleagues postulated the existence of solute exchange between the interstitial fluid of the brain parenchyma and the CSF via paravascular spaces. In 1985, Grady and colleagues suggested that cerebrospinal fluid and interstitial fluid exchange along specific anatomical pathways within the brain, with CSF moving into the brain along the outside of blood vessels. Grady's group suggested that these 'paravascular channels' were functionally analogous to peripheral lymph vessels, facilitating the clearance of interstitial wastes from the brain.[8][28] However, other laboratories at the time did not observe such widespread paravascular CSF–ISF exchange.[26][29][30][31]

The continuity between the brain interstitial fluid and the CSF was confirmed by H. Cserr and colleagues from Brown University and King's College London.[31] The same group postulated that interstitial solutes in the brain parenchyma exchange with CSF via a bulk flow mechanism, rather than diffusion. However other work from this same laboratory indicated that the exchange of CSF with interstitial fluid was inconsistent and minor, contradicting the findings of Grady and colleagues.[29][30]