It has taken a century so far for scientists to not figure out the cause of multiple sclerosis (MS). The inflammatory disease, which affects more than 2.1 million people worldwide, has been blamed on toxins, viruses and even food. Most recently, scientists have placed their bets on two major ideas: The first (and far more popular) hypothesis suggests MS begins in white matter, which influences how parts of the brain work together. White matter consists of bundles of axons covered in myelin, a white insulating fatty layer. In people with MS myelin degrades and nerve fibers are left exposed, causing problems in motor coordination and loss of senses.

The second hypothesis suggests that MS begins in the gray matter, which affects thinking and learning. The white matter hypothesis overshadows its alternative in part because white matter’s impact is easier to observe. When using a microscope to look at brain tissue, scientists are struck by the degradation in the myelin in samples from patients with MS. And when analyzing MS in the clinic, the overt symptoms experienced by a person with the disease can be attributed to the myelin. Symptoms associated with dysfunctions in gray matter are less obvious, such as the loss of an IQ point. Now, new evidence lends support to the less-favored gray matter hypothesis.

Scientists at Rutgers University in Newark tried a new approach to look into the gray matter of MS patients. They analyzed proteins in cerebrospinal fluid (CSF), which can be thought of as the central nervous system’s “blood.” By comparing the quantity of specific CSF proteins in patients who were newly diagnosed or had the relapsing remitting variety of MS with that of healthy patients, the researchers found an uneven distribution of 20 proteins among the three groups.

They discovered at least 75 percent of the proteins affect gray matter, not myelin, and used the quantities of gray matter protein associated with each group to distinguish between the healthy control and newly diagnosed MS patients. “The finding suggests there are issues happening extremely early in the gray matter that precede myelin loss,” says co-investigator Patricia Coyle, a neurologist at Stony Brook University, S.U.N.Y. The study appeared in the September 2013 PLoS One.

Without this sensitive CSF technique, researchers had struggled to observe problems in gray matter. As a result, MS patients typically are not diagnosed until they display often-debilitating symptoms relating to myelin loss. Although current treatments cannot cure the disease, they can slow its course. Thus treatment in the earliest stages could delay the onset of those symptoms. Coyle hopes the method can be documented as the first standard diagnostic test for MS. The test, however, cannot be approved for standard diagnosis until it becomes less expensive.  

In addition to offering an opportunity for earlier diagnosis, the findings also provide potential for further MS research into gray matter. “By knowing the proteins that are involved early in MS, investigators can devise new hypotheses about the problems occurring in gray matter,” says co-investigator Steven Schutzer, professor of medicine at Rutgers. He hopes researchers will look more closely into the gray matter hypothesis and find clues that could lead to more targeted therapies.

Although the findings suggest a new window into the disease, further progress in gray matter–targeted therapies might not happen for awhile. “Scientists need to figure out what’s happening in the gray matter, but we don’t know how to go about looking at those neurons and for the problems with those neurons,” Mayo Clinic neurologist and immunologist Moses Rodriquez says. “Moving the findings forward requires either a chance observation or a completely novel idea about what’s going on in the neurons.”

For now, Schutzer plans to collect more CSF samples from MS sufferers to gain a deeper understanding of the role gray matter might play.