Tag: glymphatic system

Categories : NeurologyTags :

How ‘Brain Cleaning’ While We Sleep May Lower Our Risk of Dementia

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Photo by Cottonbro on Pexels

Julia Chapman, Macquarie University; Camilla Hoyos, Macquarie University, and Craig Phillips, Macquarie University

The brain has its own waste disposal system – known as the glymphatic system – that’s thought to be more active when we sleep.

But disrupted sleep might hinder this waste disposal system and slow the clearance of waste products or toxins from the brain. And researchers are proposing a build-up of these toxins due to lost sleep could increase someone’s risk of dementia.

There is still some debate about how this glymphatic system works in humans, with most research so far in mice.

But it raises the possibility that better sleep might boost clearance of these toxins from the human brain and so reduce the risk of dementia.

Here’s what we know so far about this emerging area of research.

Why waste matters

All cells in the body create waste. Outside the brain, the lymphatic system carries this waste from the spaces between cells to the blood via a network of lymphatic vessels.

But the brain has no lymphatic vessels. And until about 12 years ago, how the brain clears its waste was a mystery. That’s when scientists discovered the “glymphatic system” and described how it “flushes out” brain toxins.

Let’s start with cerebrospinal fluid, the fluid that surrounds the brain and spinal cord. This fluid flows in the areas surrounding the brain’s blood vessels. It then enters the spaces between the brain cells, collecting waste, then carries it out of the brain via large draining veins.

Scientists then showed in mice that this glymphatic system was most active – with increased flushing of waste products – during sleep.

One such waste product is amyloid beta (Aβ) protein. Aβ that accumulates in the brain can form clumps called plaques. These, along with tangles of tau protein found in neurons (brain cells), are a hallmark of Alzheimer’s disease, the most common type of dementia.

In humans and mice, studies have shown that levels of Aβ detected in the cerebrospinal fluid increase when awake and then rapidly fall during sleep.

But more recently, another study (in mice) showed pretty much the opposite – suggesting the glymphatic system is more active in the daytime. Researchers are debating what might explain the findings.

So we still have some way to go before we can say exactly how the glymphatic system works – in mice or humans – to clear the brain of toxins that might otherwise increase the risk of dementia.

Does this happen in humans too?

We know sleeping well is good for us, particularly our brain health. We are all aware of the short-term effects of sleep deprivation on our brain’s ability to function, and we know sleep helps improve memory.

In one experiment, a single night of complete sleep deprivation in healthy adults increased the amount of Aβ in the hippocampus, an area of the brain implicated in Alzheimer’s disease. This suggests sleep can influence the clearance of Aβ from the human brain, supporting the idea that the human glymphatic system is more active while we sleep.

This also raises the question of whether good sleep might lead to better clearance of toxins such as Aβ from the brain, and so be a potential target to prevent dementia.

How about sleep apnoea or insomnia?

What is less clear is what long-term disrupted sleep, for instance if someone has a sleep disorder, means for the body’s ability to clear Aβ from the brain.

Sleep apnoea is a common sleep disorder when someone’s breathing stops multiple times as they sleep. This can lead to chronic (long-term) sleep deprivation, and reduced oxygen in the blood. Both may be implicated in the accumulation of toxins in the brain.

Sleep apnoea has also been linked with an increased risk of dementia. And we now know that after people are treated for sleep apnoea more Aβ is cleared from the brain.

Insomnia is when someone has difficulty falling asleep and/or staying asleep. When this happens in the long term, there’s also an increased risk of dementia. However, we don’t know the effect of treating insomnia on toxins associated with dementia.

So again, it’s still too early to say for sure that treating a sleep disorder reduces your risk of dementia because of reduced levels of toxins in the brain.

So where does this leave us?

Collectively, these studies suggest enough good quality sleep is important for a healthy brain, and in particular for clearing toxins associated with dementia from the brain.

But we still don’t know if treating a sleep disorder or improving sleep more broadly affects the brain’s ability to remove toxins, and whether this reduces the risk of dementia. It’s an area researchers, including us, are actively working on.

For instance, we’re investigating the concentration of Aβ and tau measured in blood across the 24-hour sleep-wake cycle in people with sleep apnoea, on and off treatment, to better understand how sleep apnoea affects brain cleaning.

Researchers are also looking into the potential for treating insomnia with a class of drugs known as orexin receptor antagonists to see if this affects the clearance of Aβ from the brain.

If you’re concerned

This is an emerging field and we don’t yet have all the answers about the link between disrupted sleep and dementia, or whether better sleep can boost the glymphatic system and so prevent cognitive decline.

So if you are concerned about your sleep or cognition, please see your doctor.

Julia Chapman, Clinical Trials Lead and Postdoctoral Research Fellow, Woolcock Institute of Medical Research and Conjoint Lecturer, Macquarie University; Camilla Hoyos, Senior Lecturer in the Centre for Sleep and Chronobiology, Macquarie University, and Craig Phillips, Associate Professor, Macquarie Medical School, Macquarie University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Categories : Lab Tests and Imaging NeurologyTags :

Scientists Definitively Reveal the Brain’s Elusive Glymphatic System

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Erin Yamamoto, MD, and Juan Piantino, MD, are among the co-authors of a new study from Oregon Health & Science University that used imaging of neurosurgery patients to definitively reveal the existence of waste-clearance pathways in the human brain known as the glymphatic system. (OHSU/Christine Torres Hicks)

Scientists have long theorised about a network of pathways in the brain that are believed to clear metabolic proteins that would otherwise build up and potentially lead to Alzheimer’s and other forms of dementia. But they had never definitively revealed this network in people – until now.

A new study involving five patients undergoing brain surgery at Oregon Health & Science University provides imaging of this network of perivascular spaces (fluid-filled structures along arteries and veins) within the brain for the first time.

“Nobody has shown it before now,” said senior author Juan Piantino, MD, associate professor of pediatrics (neurology) in the OHSU School of Medicine and a faculty member of the Neuroscience Section of the Papé Family Pediatric Research Institute at OHSU. “I was always skeptical about it myself, and there are still a lot of skeptics out there who still don’t believe it. That’s what makes this finding so remarkable.”

The findings appear in the Proceedings of the National Academy of Sciences.

The study combined the injection of an inert contrasting agent with a special type of magnetic resonance imaging to discern cerebrospinal fluid flowing along distinct pathways in the brain 12, 24 and 48 hours following surgery. In definitively revealing the presence of an efficient waste-clearance system within the human brain, the new study supports the promotion of lifestyle measures and medications already being developed to maintain and enhance it.

“This shows that cerebrospinal fluid doesn’t just get into the brain randomly, as if you put a sponge in a bucket of water,” Piantino said. “It goes through these channels.”

More than a decade ago, scientists at the University of Rochester first proposed the existence of a network of waste-clearance pathways in the brain akin to the body’s lymphatic system, part of the immune system. Those researchers confirmed it with real-time imaging of the brains of living mice. Due to its dependence on glial cells in the brain, they coined the term “glymphatic system” to describe it.

However, scientists had yet to confirm the existence of the glymphatic system through imaging in people.

Pathways revealed in patients

The new study examined five OHSU patients who underwent neurosurgery to remove tumours in their brains between 2020 and 2023. In each case, the patients consented to having a gadolinium-based inert contrasting agent injected through a lumbar drain used as part of the normal surgical procedure for tumour removal. The tracer would be carried with cerebrospinal fluid into the brain.

Afterward, each patient underwent magnetic resonance imaging, or an MRI, at different time points to trace the spread of cerebrospinal fluid.

Rather than diffusing uniformly through brain tissue, the images revealed fluid moving along pathways — through perivascular spaces in clearly defined channels. Researchers documented the finding with a specific kind of MRI known as fluid attenuated inversion recovery, or FLAIR. This type of imaging is sometimes used following the removal of tumors in the brain. As it turns out, it also revealed the gadolinium tracer in the brain, whereas the standard MRI sequences did not.

“That was the key,” Piantino said.

“You can actually see dark perivascular spaces in the brain turn bright,” said co-lead author Erin Yamamoto, MD, a resident in neurological surgery in the OHSU School of Medicine. “It was quite similar to the imaging the Rochester group showed in mice.”

Clearing waste from the brain

Scientists believe this network of pathways effectively flushes the brain of metabolic wastes generated by its energy-intensive work. Wastes include proteins such as amyloid and tau, which have been shown to form clumps and tangles in brain images of patients with Alzheimer’s disease.

Emerging research suggests medications that may be useful, but much of the focus around the glymphatic system has revolved around lifestyle-based measures to improve the quality of sleep, such as maintaining a regular sleep schedule, establishing a relaxing routine, and avoiding screens in the bedroom before bed. Especially at night during deep sleep, researchers believe a well-functioning glymphatic system efficiently carries waste proteins toward veins exiting the brain.

“People thought these perivascular spaces were important, but it had never been proved,” Piantino said. “Now it has.”

The authors credited the late Justin Cetas, MD, PhD, who initiated the study as an OHSU neurosurgeon before leaving the university to become chair of neurological surgery at his alma mater, the University of Arizona Health Sciences Center in Tucson. He died in a motorcycle accident in 2022.

Source: Oregon Health & Science University

Categories : NeurologyTags :

Navigating the Maze of the Brain’s Glymphatic System

On By ModernMedia
Photo by Robina Weermeijer on Unsplash

Like the lymphatic system in the body, the glymphatic system in the brain clears metabolic waste and distributes nutrients and other important compounds. Impairments in this system may contribute to brain diseases, such as neurodegenerative diseases and stroke.

A team of researchers has found a noninvasive and nonpharmaceutical method to influence glymphatic transport using focused ultrasound, opening the opportunity to use the method to further study brain diseases and brain function. Their findings are published in PNAS.

Hong Chen, associate professor of biomedical engineering in McKelvey Engineering and of neurological surgery in the School of Medicine, and her team, including Dezhuang (Summer) Ye, a postdoctoral research associate, and Si (Stacie) Chen, a former postdoctoral research associate, found the first direct evidence that focused ultrasound, combined with circulating microbubbles (FUSMB) could mechanically enhance glymphatic transport in the mouse brain.

Focused ultrasound can penetrate the scalp and skull to reach the brain and precisely target a defined region within the brain. Previously, Chen’s team found that microbubbles injected into the bloodstream amplify the effects of the ultrasound waves on the blood vessels and generate a pumping effect, which helps with the accumulation of intranasally delivered agents in the brain, such as drugs or gene therapy treatments.

“Intranasal delivery provides a novel, noninvasive route to investigate the glymphatic pathway in intact brains,” Chen said. “This route for investigating glymphatic transport has the potential to be utilised in the study of glymphatic function in humans, which is currently limited by the absence of noninvasive approaches to access the glymphatic system.”

In the new research, the team administered a fluorescently labelled tracer intranasally. Then they administered focused ultrasound waves aimed deep in the brain at the thalamus after intravenous injection of microbubbles. When they conducted 3D imaging of the brain tissue on the treated side, they found that FUSMB boosted the transport of the tracer in the perivascular space.

They compared this with three control groups with various combinations of focused ultrasound, microbubbles and the tracer. All of the mice in the three control groups showed lower tracer accumulation, which verified to the team that the enhanced tracer transport was the result of the focused ultrasound with microbubbles.

To further validate their results, they used the FUSMB treatment after injecting the tracer directly to the cerebral spinal fluid, an invasive yet commonly used method. They found that FUSMB also enhanced the transport of tracers along the vessels at the focused-ultrasound targeted brain site by about two- to threefold compared with the non-targeted side.

“Regardless of whether tracers were delivered via the intranasal or injected route, FUSMB consistently improved glymphatic transport,” Ye said. “Our study using confocal microscopy imaging combined with brain-tissue clearing obtained direct evidence that unequivocally proved that FUSMB enhanced the glymphatic transport of a labeled protein agent in mice.”

The team also investigated various types of vessels, including arterioles, capillaries and venules, that facilitate FUSMB-enhanced transport of the tracer using both intranasal and injected delivery of the tracer. They saw improved glymphatic transport of the tracer in both arterioles and capillaries with both types of delivery. They found that the fluorescence intensity was higher along arterioles than capillaries and venules.

“This study opens new opportunities to use ultrasound combined with microbubbles as a noninvasive and nonpharmacological approach to manipulate glymphatic transport,” Ye said. “Focused ultrasound-activated microbubbles have the promise to enhance waste clearance in the brain and potentially mitigate brain diseases caused by impairments in glymphatic system function.”

Chen said the team will now focus on applying this noninvasive and nonpharmacological method for brain waste clearance to potentially combat neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases.

Source: University of Washington in St. Louis