New Imaging Approach Reveals Lymph System in Brain

Posted on October 17th, 2017 by Dr. Francis Collins

Considering all the recent advances in mapping the complex circuitry of the human brain, you’d think we’d know all there is to know about the brain’s basic anatomy. That’s what makes the finding that I’m about to share with you so remarkable. Contrary to what I learned in medical school, the body’s lymphatic system extends to the brain—a discovery that could revolutionize our understanding of many brain disorders, from Alzheimer’s disease to multiple sclerosis (MS).

Researchers from the National Institute of Neurological Disorders and Stroke (NINDS), the National Cancer Institute (NCI), and the University of Virginia, Charlottesville made this discovery by using a special MRI technique to scan the brains of healthy human volunteers [1]. As you see in this 3D video created from scans of a 47-year-old woman, the brain—just like the neck, chest, limbs, and other parts of the body—possesses a network of lymphatic vessels (green) that serves as a highway to circulate key immune cells and return metabolic waste products to the bloodstream.

How could the brain’s lymphatic system have been missed for all these years? Actually, some had suggested centuries ago that lymphatic vessels surrounded the brain. But in the absence of supporting data, those ideas were largely forgotten or dismissed as wrong. Scientists generally assumed the brain, unlike the rest of the body, had a special ability to rid itself of waste products through the cerebral spinal fluid (CSF). (In fact, some of the brain’s waste products probably do make their way to the bloodstream via CSF.) Also, lymphatic vessels aren’t readily apparent in standard microscopic images, and aren’t visible on standard MRI scans because they track right alongside much larger and more conspicuous blood vessels.

That thinking began to change a couple of years ago. First, using a high-powered microscope to examine the brains of mice, an NIH-funded team at UVA discovered vessel-like structures associated with the meninges, a leathery layer of protective tissue that surrounds the brain. Further study led those researchers to conclude that those vessels were carrying lymphatic fluid [2].

As luck would have it, NINDS intramural researcher Daniel Reich happened to see a talk by Jonathan Kipnis, one of the researchers who made the mouse discovery. Reich didn’t know a lot about the lymphatic system, but, as a neurologist and radiologist studying MS and other inflammatory brain diseases, he did know a lot about the immune system, the brain, and brain imaging. It got him thinking: what if the findings in mice applied to humans?

So, Reich and his colleagues decided to join forces with the UVA group. They knew that in order to search for lymph vessels in the brains of living humans, they’d need to find a way to tone down the brightness of the brain’s blood vessels on MRI scans. Fortunately, they had a few imaging tricks up their sleeves.

As described in their paper published in the journal eLife, the researchers injected a dye called gadobutrol into five healthy people before taking pictures of their brains with a standard clinical MRI scanner. While the dye makes blood vessels light up on MRI scans, it’s also known that some of the gadobutrol leaks out of blood vessels. The researchers hypothesized that if lymph vessels were running alongside blood vessels in the human brain (as they do in mice), then some gadobutrol should find its way into the lymph vessels, causing them to light up too.

When the researchers scanned the brains of people in the usual manner, all they could make out was blood vessels. That was no surprise. But, when they tuned the MRI scanner a bit differently—using an approach called black-blood imaging to hide blood vessels—another system of smaller but equally bright vessels appeared. Voila! The human brain did indeed have lymph vessels.

As confirmation, the researchers did another round of MRI scans with a dye containing larger molecules that were much less able to leak out of blood vessels and thereby make their way into lymph vessels. Under those conditions, the smaller vessels were not visible.

This is a very cool discovery, but what does it mean for people suffering from brain disorders? Because the lymphatic system plays a vital role in immune response, Reich says the new knowledge could be important for understanding, treating, and preventing brain disorders involving immune-related inflammation. Such conditions include MS, stroke, Alzheimer’s disease, Parkinson’s disease, and maybe even some mental health conditions.

For example, Reich is now eager to compare brain lymphatic system function in people with MS versus that in healthy folks. Also, because the NIH researchers have freely shared their innovative approach for visualizing the brain’s lymph vessels, neuroscientists all around the world can now begin to explore similar questions in the groups of patients they study.

References:

[1] Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. Elife. 2017 Oct 3;6.

[2] Structural and functional features of central nervous system lymphatic vessels. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Nature. 2015 Jul 16;523(7560):337-341.

Links:

Multiple Sclerosis Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Magnetic Resonance Imaging (National Institute of Biomedical Imaging and Bioengineering/NIH)

Daniel Reich (National Institute of Neurological Disorders and Stroke/NIH)

Kipnis Lab (University of Virginia, Charlottesville)

NIH Funding: National Institute of Neurological Disorders and Stroke; National Cancer Institute; National Institute on Aging