Glymphatic system
The glymphatic system, glymphatic clearance pathway or paravascular system is an organ system for metabolic waste removal in the central nervous system of vertebrates. According to this model, cerebrospinal fluid, an ultrafiltrated plasma fluid secreted by choroid plexuses in the cerebral ventricles, flows into the paravascular space around cerebral arteries, contacts and mixes with interstitial fluid and solutes within the brain parenchyma, and exits via the cerebral venous paravascular spaces back into the subarachnoid space. The pathway consists of a para-arterial influx mechanism for CSF driven primarily by arterial pulsation, which "massages" the low-pressure CSF into the denser brain parenchyma, and the CSF flow is regulated during sleep by changes in parenchyma resistance due to expansion and contraction of the extracellular space. Clearance of soluble proteins, metabolites and excess extracellular fluid is accomplished through convective bulk flow of ISF, facilitated by astrocytic aquaporin 4 water channels.
The name "glymphatic system" was coined by the Danish neuroscientist Maiken Nedergaard in recognition of its dependence upon glial cells and the similarity of its functions to those of the peripheral lymphatic system.
Proposed structure
In a study published in 2012, a group of researchers from the University of Rochester, headed by Maiken Nedergaard, used in-vivo two-photon imaging of small fluorescent tracers to monitor the flow of subarachnoid CSF into and through the brain parenchyma. The two-photon microscopy allowed the Rochester team to visualize the flux of CSF in living mice, in real time, without needing to puncture the CSF compartment. According to findings of that study, subarachnoid CSF enters the brain rapidly, along the paravascular spaces surrounding the penetrating arteries, then exchanges with the surrounding interstitial fluid. Similarly, interstitial fluid is cleared from the brain parenchyma via the paravascular spaces surrounding large draining veins.Paravascular spaces are CSF-filled channels formed between the brain blood vessels and leptomeningeal sheathes that surround cerebral surface vessels and proximal penetrating vessels. Around these penetrating vessels, paravascular spaces take the form of Virchow-Robin spaces. Where the Virchow-Robin spaces terminate within the brain parenchyma, paravascular CSF can continue traveling along the basement membranes surrounding arterial vascular smooth muscle, to reach the basal lamina surrounding brain capillaries. CSF movement along these paravascular pathways is rapid and arterial pulsation has long been suspected as an important driving force for paravascular fluid movement. In a study published in 2013, J. Iliff and colleagues demonstrated this directly, using in vivo two-photon microscopy. The authors reported that when cerebral arterial pulsation was either increased or decreased, the rate of paravascular CSF flux in turn increased or decreased, respectively.
Astrocytes extend long processes that interface with neuronal synapses, as well as projections referred to as 'end-feet' that completely ensheathe the brain's entire vasculature. Astrocytes are known to facilitate changes in blood flow and have long been thought to play a role in waste removal in the brain. Astrocytes express water channels called aquaporins. Until 2000, no physiological function had been identified that explained their presence in the mammalian CNS. Aquaporins are membrane-bound channels and regulate the flux of water into and out of cells. Relative to simple diffusion, they increases water permeability 3– to 10-fold.
The two types of aquaporins expressed in the CNS are aquaporin-1, which is expressed by specialized epithelial cells of the choroid plexus, and aquaporin-4, which is expressed by astrocytes. Aquaporin-4 expression in astrocytes is highly polarized to the endfoot processes ensheathing the cerebral vasculature. Up to 50% of the vessel-facing endfoot surface that faces the vasculature is occupied by orthogonal arrays of AQP4.
In 2012, it was shown that AQP4 is essential for paravascular CSF–ISF exchange. Analysis of genetically modified mice that lacked the AQP4 gene revealed that the bulk flow-dependent clearance of interstitial solutes decreases by 70% in the absence of AQP4. Based upon this role of AQP4-dependent glial water transport in the process of paravascular interstitial solute clearance, Iliff and Nedergaard termed this brain-wide glio-vascular pathway the "glymphatic system".
Function
Waste clearance during sleep
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. 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. The flow is elicited by slow variations in the release of noradrenaline by the locus coeruleus.Lipid transport
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.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 to carry lipids to the liver.
Clinical significance
Pathologically, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease are all characterized by the progressive loss of neurons, cognitive decline, motor impairments, and sensory loss. Collectively these diseases fall within a broad category referred to as proteinopathies due to the common assemblage of misfolded or aggregated intracellular or extracellular proteins. According to the prevailing amyloid hypothesis of Alzheimer's disease, the aggregation of amyloid-beta into extracellular plaques drives the neuronal loss and brain atrophy that is the hallmark of Alzheimer's dementia. Although the full extent of the involvement of the glymphatic system in Alzheimer's disease and other neurodegenerative disorders remains unclear, researchers have demonstrated through experiments with genetically modified mice that the proper function of the glymphatic clearance system was necessary to remove soluble amyloid-beta from the brain interstitium. In mice that lack the AQP4 gene, amyloid-beta clearance is reduced by approximately 55 percent.The glymphatic system also may be impaired after acute brain injuries such as ischemic stroke, intracranial hemorrhage, or subarachnoid hemorrhage. In 2014, a group of researchers from the French Institute of Health and Medical Research demonstrated by MRI that the glymphatic system was impaired after subarachnoid hemorrhage, because of the presence of coagulated blood in the paravascular spaces. Injection of tissue plasminogen activator in the CSF improved glymphatic functioning. In a parallel study, they also demonstrated that the glymphatic system was impaired after ischemic stroke in the ischemic hemisphere, although the pathophysiological basis of this phenomenon remains unclear. Notably, recanalization of the occluded artery also reestablished the glymphatic flow.
The glymphatic system may also be involved in the pathogenesis of amyotrophic lateral sclerosis.