Long-Theorized Waste-Clearing Pathway Uncovered in the Human Brain

The glymphatic system, a long-theorized waste-clearing pathway in the brain, has been revealed for the first time in humans, in a new study by Oregon Health and Science University (OSHU) researchers.

The study is published in PNAS.

Translating findings from rodents to humans

Previous research has revealed a lymphatic waste clearance system in the human brain. However, another system exists in rodents – the glymphatic system – as revealed by researchers from the University of Rochester. But this system had not been definitively shown in humans, until now.

This glymphatic system earns its name from its dependence on glial cells, which support neurons in the central nervous system (CNS). It uses a network of fluid-filled spaces along arteries and veins called perivascular spaces. Studies in rats and mice show that cerebrospinal fluid (CSF) flows from these perivascular spaces into the brain tissue, allowing soluble by-products from the CNS to be cleared.

“This system was clearly shown previously in mice through pioneering work more than a decade ago by researchers at the University of Rochester who originally coined the term for the glymphatic system,” lead study author Erin Yamamoto, resident in neurological surgery in the OSHU School of Medicine, told Technology Networks. “Mice share certain biological similarities with humans, but not everything in mice translates to humans.”

Impairments in the glymphatic pathway are believed to be involved in sleep dysfunction, traumatic brain injury and Alzheimer’s disease. Given the potential implications for our understanding of disease, the new study by OSHU researchers revealed the existence of a human glymphatic pathway using specialized brain imaging.

Brain imaging reveals waste pathways

Yamamoto and the team recruited five patients in 2020–2023 who were about to undergo neurosurgery to remove brain tumors.

Each patient had a specific type of MRI after their surgery known as FLAIR (fluid-attenuated inversion recovery). The FLAIR MRIs traced the spread of cerebrospinal fluid into the brain using a gadolinium-based contrast agent.

These scans revealed that the fluid moved along defined pathways – i.e., through the perivascular spaces – instead of diffusing uniformly through the brain tissue. Crucially, the FLAIR MRI technique revealed the gadolinium tracer in the brain, whereas standard MRI did not.

“MRI technology has significantly improved, thus allowing for visualization of perivascular spaces,” Yamamoto explained. “Other research groups have also performed similar MRI studies after injecting tracer into spinal fluid; however, use of FLAIR MRI was the missing piece.”

“People thought these perivascular spaces were important, but it had never been proved,” said Juan Piantino, senior author of the study and associate professor of pediatrics (neurology) at OSHU. “Now it has.”

With the skepticism surrounding the existence of this system in humans diminishing, Yamamoto explained some of the ways that the glymphatic system may influence human health: “We believe a well-functioning glymphatic system works to efficiently clear wastes, such as amyloid and tau, from brain tissue,” she said. “The directionality and movement of the fluid is believed at least in part to be driven by arterial pulsations from the cardiac cycle and facilitated by deep sleep.”

Building upon glymphatic system findings

There are several limitations to the study that Yamamoto highlighted: “The sample size was small, and it involved patients whose normal circulation may have been slowed because of their recent surgery. The manner in which the MRIs were performed were not consistent across all patients due to their unique postoperative courses and the complex nature of working with hospitalized patients.”

Nonetheless, the study’s findings could open avenues for investigating how these pathways effectively flush the brain of metabolic waste products, potentially even shedding light on factors involved in Alzheimer’s disease.

“This study builds scientific support for exploring avenues to maintain or enhance this system to forestall neurodegenerative conditions that may be caused or exacerbated by a poorly functioning glymphatic system,” Yamamoto said.

Reference: Yamamoto EA, Bagley JH, Geltzeiler M, et al. The perivascular space is a conduit for cerebrospinal fluid flow in humans: A proof-of-principle report. PNAS. 2024;121(42):e2407246121. doi: 10.1073/pnas.2407246121

 

Dr. Erin Yamamoto was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.

About the interviewee:

Dr. Erin Yamamoto is a sixth-year resident in neurosurgery at OSHU. She majored in neuroscience at Colorado College before earning a combined MD and MS degree at Case Western Reserve University in 2019. She also worked as a research fellow at the National Eye Institute’s Neurobiology, Neurodegeneration and Repair Lab studying retinal degeneration and hydrocephalus.