“The traditional way of thinking is that MS is primarily a white matter disease,” says Lael Stone, MD, formerly a neurologist specializing in multiple sclerosis (MS) at the Cleveland Clinic in Ohio. But “most [experts] in MS at this point would say that there is clearly involvement of both white and gray matter,” says Dr. Stone. Still, “you could put 10 MS specialists in a room, and they would have a hard time agreeing on which is more important and which comes first.”
White Matter Consists Mainly of Nerve Fibers
White matter appears white because the protective wrapping around nerve fibers, or axons, is a pale, fatty tissue called myelin. “Axons are like the electric wires of the brain," says Rhonda Voskuhl, MD, professor of neurology at the UCLA Brain Research Institute and director of the UCLA Multiple Sclerosis Program in Los Angeles. In MS, the immune system attacks the myelin in the brain, spinal cord, and optic nerves. The attack causes inflammation that eventually leads to sclerosis, which is the medical term for scarring. (That’s how MS got its name.) “When MS attacks these parts of the brain, it’s like stripping the rubber off the wires. That slows down conduction speed and causes the types of MS symptoms that come and go,” says Dr. Voskuhl. “An attack may last for weeks or months, but then the inflammation cools off, and the area recovers completely or partially.” “The white matter carries messages from point A to point B,” Stone says. “The gray matter is point A and point B.” As MS progresses, changes occur in the gray matter that are different from those occurring in the white matter. “If you cut off the connections between nerve cells, they eventually die," Voskuhl explains. “This causes a shrinking of brain tissue, called gray matter atrophy. MS causes inflammation in white matter and atrophy in gray matter. You can measure atrophy by actual loss of brain volume.” But demyelination and lesions can also happen in gray matter, even if this isn’t visible using conventional magnetic resonance imaging (MRI) scans, according to Léorah Freeman, MD, PhD, a neurologist and assistant professor at Dell Medical School at the University of Texas at Austin. In fact, Dr. Freeman says, “We know from postmortem studies that in the most severe cases, up to 70 percent of the gray matter can be demyelinated” in people with MS.
Newer Types of MRI and PET Scans Reveal Disease Progression in the MS Brain
Researchers and doctors who treat MS commonly use MRI scans to study the brain. MRI is imaging created with computers and radio wave energy. New types of MRI provide more detail, making it easier to see gray matter. Magnetic resonance spectroscopy shows areas of the brain where proteins found only inside neurons are located. Functional MRI (fMRI) makes images of the brain while a person is doing a specific task, like reading. When fewer areas light up during this test, it may be a sign of gray matter atrophy. Gray matter damage has been shown to play an important role in MS disease progression, according to a study study published in July 2013 in the journal Annals of Neurology that followed more than 400 people with relapsing-remitting MS. Using a model that included a patient’s age, gray matter lesions, and gray matter atrophy, researchers were able to correctly predict MS progression in about 94 percent of participants who maintained relapsing-remitting MS status, and 88 percent of those who transitioned to the secondary-progressive stage. Knowledge of how gray matter damage affects MS has lagged behind what’s known about white matter, due to the limitations of conventional imaging techniques. “It’s easy to see white matter inflammation, because it lights up like a Christmas tree on MRI,” Stone says. “Gray matter atrophy is harder to see. Eventually, it shows up as an increase in the fluid-filled parts of the brain as the brain shrinks. But that can be confusing, because the truth is that everybody’s brain shrinks over time — with or without MS.” Freeman notes that newer imaging techniques, like positron emission tomography (PET), can help identify gray matter changes that may not be visible on a conventional MRI. In a small pilot study published in October 2015 in the journal Annals of Neurology, a research team led by Freeman found that PET scans could effectively map and reveal measurements of neuronal damage in the gray matter of people with various stages of MS.
Symptoms of Gray and White Matter Disease
“In general, white matter disease causes acute MS symptoms, like numbness and weakness," Stone says. “Gray matter disease causes progressive symptoms, like fatigue and memory loss. These higher brain functions are called cognitive functions. Most MS disability actually comes from cognitive dysfunction.” Voskuhl provides another angle: “I think it makes sense to think of some white matter damage like inflammation as temporary, and some gray matter damage like neuron loss as permanent,” she says. “It’s important to know that cognitive changes in MS are not like in Alzheimer’s disease. They don’t affect a person’s intelligence, long-term memory, or their ability to read or carry on a conversation.” It’s the cumulative damage to both gray and white matter that adds up to MS symptoms, Stone adds. The problem is that even with increasingly detailed imaging techniques, visible changes in the brain don’t correlate exactly with symptoms like fatigue or cognitive impairment. “Part of the whole discussion is that we are missing something in MS, and we are constantly trying to figure out what it is we are missing,” says Stone. Freeman is optimistic that advances in imaging will make it easier to pinpoint how communication between different areas of the brain contributes to a wide range of MS symptoms. “We’re trying to make more correlations between specific symptoms and specific locations of lesions or damage,” she notes.
Better Imaging May Lead to Better Drugs for MS
Gaining a better understanding of how MS operates in the brain is critical to developing the next generation of MS drugs, according to Voskuhl. “We have drugs that can suppress the immune system, reduce MS attacks, and decrease white matter damage. But what we need now are drugs that prevent or reverse long-term disability of all types, including not only cognition but also walking, balance, and vision," Voskuhl says. “Research focused on gray matter protection may be the critical next step in this goal.” Freeman notes that recent advances in imaging, and the better understanding of gray matter damage that they allow, are already affecting how trials of potential new MS drugs are conducted. “Clinical trials are more consistently looking at the impact of the drug on brain atrophy” in different gray matter structures, Freeman says, “because those are meaningful end points” that the U.S. Food and Drug Administration (FDA) is interested in. Aside from informing new drug development, advances in imaging may also prove useful to doctors in deciding what course of treatment is best for an individual patient, according to Freeman. Her lab is studying computing techniques to extract more meaningful information from conventional MRIs that are already part of the standard of MS care. “Right now, the information we’re using from these MRIs to monitor therapy is [whether] patients develop new or active lesions within the white matter,” Freeman explains. “I think we could be using MRI in a different way, to maybe predict treatment response before we even start therapy.”
Artificial Intelligence Could Play a Role in MS Treatment Advances
This vision of MS imaging and treatment could involve using artificial intelligence (AI) technologies to look at the entire brain in MRI scans, and predict individual outcomes and responses to different MS drugs. In this way, AI could help doctors know “what therapy we should initiate, or when it is time to switch, before patients fail their medication,” says Freeman, as part of a “move from a trial-and-error approach to therapy, and more into a personalized, precision-medicine approach to therapy.” The best way to get there, the experts agree, is to keep developing and refining imaging techniques that advance our knowledge of the MS brain. Additional reporting by Quinn Phillips.
