Scientists have long theorized about a network of pathways in the brain that are believed to clear out metabolic proteins that would otherwise build up and potentially lead to Alzheimer’s disease and other forms of dementia. But they had never definitively revealed this network in humans -; 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 -; in the brain for the first time.
No one has shown it yet. I was always skeptical about it myself, and there are still many skeptics who still don’t believe it. That is what makes this finding so remarkable.”
Juan Piantino, MD, senior author, associate professor of pediatrics (neurology) at the OHSU School of Medicine and faculty member of the Department of Neuroscience at the Papé Family Pediatric Research Institute at OHSU
The research published today in the Proceedings of the National Academy of Sciences.
The study combined the injection of an inert contrast agent with a special type of magnetic resonance imaging to distinguish cerebrospinal fluid that flows along different routes in the brain 12, 24 and 48 hours after surgery. By definitively revealing the presence of an efficient waste disposal system in the human brain, the new study supports the promotion of lifestyle measures and medications already being developed to maintain and improve it.
“This shows that cerebrospinal fluid doesn’t just randomly enter the brain, like putting 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 disposal pathways in the brain, similar to the body’s lymphatic system, part of the immune system. Those researchers confirmed this with real-time imaging of the brains of living mice. Due to the brain’s reliance on glial cells, they coined the term “glymphatic system” to describe it.
However, scientists had yet to confirm the existence of the glymphatic system through imaging in humans.
Pathways revealed in patients
The new study examined five OHSU patients who underwent neurosurgery between 2020 and 2023 to remove tumors in their brains. In each case, patients consented to a gadolinium-based inert contrast agent being injected through a lumbar drain, used as part of the normal surgical procedure. for tumor removal. The tracer would be carried to the brain with cerebrospinal fluid.
Then, each patient underwent magnetic resonance imaging, or an MRI, at different times to track the spread of cerebrospinal fluid.
Instead of diffusing evenly through the brain tissue, the images showed fluid moving along pathways -; through perivascular spaces in well-defined channels. Researchers documented the finding with a specific type of MRI known as Fluid Attenuated Inversion Recovery, or FLAIR. This type of imaging is sometimes used after the removal of tumors in the brain. It turned out that it also revealed the gadolinium tracer in the brain, while the standard MRI sequences did not.
“That was the key,” Piantino said.
“You can see dark perivascular spaces in the brain become bright,” says co-lead author Erin Yamamoto, MD, a physician in neurological surgery at the OHSU School of Medicine. “It was quite similar to the imaging that the Rochester group showed in mice.”
Clearing the waste products from the brain
Scientists believe that this network of pathways effectively clears the brain of metabolic waste generated by the energy-intensive work. Waste products 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 shows that medications can be helpful, but much of the attention surrounding the glymphatic system has focused on lifestyle-based measures to improve sleep quality, such as maintaining a regular sleep schedule, establishing a relaxing routine, and avoiding screens during sleep. bedroom before going to sleep. Particularly at night during deep sleep, researchers believe that a well-functioning glymphatic system efficiently transports waste proteins to the arteries leaving the brain.
“People thought these perivascular spaces were important, but it was never proven,” Piantino said. “Now it is.”
The authors mention the late Justin Cetas, M.D., Ph.D., who initiated the study as an OHSU neurosurgeon before leaving OHSU to become chairman of neurological surgery at his alma mater, the University of Arizona Health Sciences Center in Tucson. He died in 2022 in a motorcycle accident.
In addition to Piantino and Yamamoto, co-lead author Jacob H. Bagley, MD, of OHSU and Aurora St. Luke’s Medical Center in Milwaukee; and co-authors Mathew Geltzeiler, MD, associate professor of otolaryngology (head and neck surgery) at the OHSU School of Medicine; Olabisi R. Sanusi, MD, assistant professor of neurological surgery at the OHSU School of Medicine; Aclan Dogan, MD, professor of neurological surgery (skull base and cerebrovascular) at the OHSU School of Medicine; and Jesse J. Liu, MD, assistant professor of neurological surgery (skull base and cerebrovascular) at the OHSU School of Medicine.
The research was supported by a Medical Research Foundation of Oregon Early Clinical Investigator grant; the North American Skull Base Society; and by the National Heart, Lung, and Blood Institute of the National Institutes of Health, grants K23HL150217 and R21HL167077. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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Magazine reference:
Yamamoto, E.A. et al. (2024) The perivascular space is a conduit for cerebrospinal fluid flow in humans: a proof-of-principle report. PNAS. doi.org/10.1073/pnas.2407246121.