Evidence of previously unrecognized hub in the brain's lymphatic drainage system revealed

How does the brain take out its trash? That is the job of the brain's lymphatic drainage system, and efforts to understand how it works have pushed the boundaries of brain-imaging technologies.

A new study in iScience by researchers at the Medical University of South Carolina reveals, for the first time in humans, evidence of a previously unrecognized hub in the brain's lymphatic drainage system – the middle meningeal artery (MMA). Taking advantage of a NASA partnership that provided access to real-time MRI technologies originally developed to study how spaceflight affects fluid dynamics in the human brain, the MUSC research team, led by Onder Albayram, Ph.D., tracked cerebrospinal and interstitial fluid flow along the MMA in five healthy participants over a six-hour period. They found that the drainage flow of the cerebrospinal fluid was passive, suggesting lymphatic rather than blood flow. Blood would have had a faster, more dynamic flow.

We saw a flow pattern that didn't behave like blood moving through an artery; it was slower, more like drainage, showing that this vessel is part of the brain's cleanup system."

Onder Albayram, Ph.D., Associate Professor, Department of Pathology and Laboratory Medicine, MUSC

The central nervous system, composed of the brain and spinal cord, is surrounded by a multi-layer protective membrane known as the meninges. Albayram has been working for more than a decade to describe the brain's meningeal lymphatic vessels, which he thinks are essential for moving waste out of the brain and into the peripheral lymphatic system, where it can be eliminated from the body.

Until about a decade ago, it was thought that these meningeal membranes isolated the brain from the rest of the body's immune system, in particular the lymphatic system. Albayram's work is changing this paradigm by showing that these membranes contain lymphatic vessels integrated into the periphery. Understanding the exchange of fluids between the brain and the rest of the body is essential to expanding our options to prevent and treat psychiatric and neurological diseases.

Albayram was among the first to visualize meningeal lymphatic vessels in humans, as reported in a 2022 article in Nature Communications. The study in iScience captures the flow of fluids within the meningeal lymphatic architecture deep within the human brain in real time and validates these findings through advanced imaging of postmortem human tissue.

To confirm what they saw on MRI, Albayram's team examined human brain tissue under extremely high-resolution imaging. Working with scientists at Cornell University, the team used an advanced technique that allows researchers to see many different cell types at once. This detailed mapping showed that the area around the MMA is lined with cells typically found in the body's lymphatic vessels, the channels responsible for clearing waste.

These results confirmed that the slow-moving fluid seen on MRI was indeed flowing through true lymphatic vessels, not blood vessels – linking the brain images directly to cellular evidence.

Core to Albayram's work is a focus on making observations in humans first, before expanding out into experimental models, such as mice, rather than the other way around. One key element of this study is that it was conducted in healthy people. Having a clear understanding of how these structures function under normal conditions is essential for recognizing what changes when things go wrong – for example, after a traumatic brain injury or during neurodegenerative conditions.

The implications of this discovery extend to aging, neuroinflammation, brain injury, Alzheimer's disease and even psychiatric disorders. Albayram is already pursuing research based on key observations of the lymphatic drainage architecture in patients with neurodegenerative diseases, with the goal of developing better ways to diagnose these complex diseases earlier, prevent them and design new treatments.

"A major challenge in brain research is that we still don't fully understand how a healthy brain functions and ages," said Albayram. "Once we understand what 'normal' looks like, we can recognize early signs of disease and design better treatments."