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Glymphatic System May Play Key Role in Removing Brain Waste


SAN DIEGO—A recently discovered system known as the glymphatic system clears waste from the brain. It is most active during sleep and may have implications in headache and in neurodegenerative diseases associated with pathologic protein aggregation, including Parkinson’s disease and Alzheimer’s disease, said Helene Benveniste, MD, PhD, Professor of Anesthesiology and Vice Chair for Research at Stony Brook School of Medicine in New York. Data suggest that sleep, posture, and brain injury may affect this waste removal system.

Helene Benveniste, MD, PhD

“We look at the glymphatic pathway as a bit of an overlooked compartment of the vasculature or the perivascular space that is … facilitating solute and waste removal,” Dr. Benveniste said at the 58th Annual Scientific Meeting of the American Headache Society. Although most studies of the glymphatic system so far have been performed in rodents, “data are starting to come out showing that this system is also present in humans,” she said.

A Brainwide Pathway

The glymphatic system, which gets its name from the glial cells and lymphatic system that it mimics, may explain how the brain—one of the most metabolically active organs—clears excess fluids, solutes, and waste products without authentic lymph vessels, Dr. Benveniste said. The system consists of a brainwide pathway that facilitates the exchange of CSF with interstitial fluid to clear interstitial waste from the brain parenchyma. The waste is moved into perivenous pathways and ultimately cleared via cervical lymphatic vessels.

Researchers first described the concept of the glymphatic system in Science Translational Medicine in 2012. They injected fluorescent tracers into the cisterna magna and fluorescent-tagged amyloid beta into brain parenchyma of mice and observed distribution of the tracers along the glymphatic pathway using two-photon imaging. The paper’s senior author, Maiken Nedergaard, MD, DMSc, Professor of Neurosurgery and Translational Neuromedicine at the University of Rochester in New York, contacted Dr. Benveniste to develop a way to visualize the system using MRI, which they accomplished using a 9.4-T system and small molecular weight contrast dye injected via an intrathecal catheter inserted in the cisterna magna.

In 2015, researchers in Norway published a case report in Acta Radiologica Open supporting the existence of a glymphatic system in humans. They administered intrathecal gadobutrol to diagnose a CSF leak in a patient. The patient underwent 3D T1-weighted imaging at one hour and 4.5 hours. The distribution of gadobutrol into the brain was consistent with that observed in rodents and supports the concept of a glymphatic pathway in the human brain, the authors concluded.

Researchers still are evaluating the glymphatic system’s role in maintaining brain health and how it differs in humans and rodents. Aquaporin channels, which are crucial in facilitating CSF transport from the periarterial space and into the interstitial space to drive waste removal via the glymphatic pathway, may be positioned differently in rodents and humans, Dr. Benveniste said. In addition, waste clearance may be orders of magnitude slower in humans due to brain size and complexity, she said.

Factors Affecting Glymphatic Flow

In mice genetically modified to lack aquaporin channels, convective flow and waste removal via the glymphatic pathway are slowed down immensely.

After traumatic brain injury, glymphatic pathway function was reduced by approximately 60% in mice for at least one month, Iliff et al reported in the Journal of Neuroscience in 2014. In mice without aquaporin channels, however, glymphatic pathway dysfunction was further exacerbated, and those animals developed neurofibrillary pathology and neurodegeneration.

One of the most important factors affecting glymphatic flow is interstitial space volume, which increases by 40% to 60% during sleep, Dr. Benveniste said. Natural sleep and certain types of anesthetics dramatically increase interstitial space volume, Xie et al reported in Science in 2013. Likewise, awaking sleeping mice sharply reduces glymphatic flow. The authors concluded, “the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake CNS.”

Injecting a norepinephrine receptor antagonist intrathecally can stimulate intense glymphatic transport in animals in the awake state, indicating that noradrenergic tone may be responsible for the process, Dr. Benveniste said.

She and her colleagues studied glymphatic clearance in mice anesthetized with dexmedetomidine, which induces a state similar to stage 2 sleep, versus the inhalational anesthetic isoflurane. Glymphatic processing was much greater in rodents that received dexmedetomidine.

Sleep Position

Hedok Lee, PhD, Clinical Assistant Professor of Anesthesiology at Stony Brook School of Medicine, Dr. Benveniste, and colleagues studied the effect of body posture on brain glymphatic transport in rats. They found that glymphatic transport and amyloid beta clearance were most efficient in the lateral and supine positions, while the prone position (ie, most upright and mimicking awake posture) resulted in slower clearance.


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