MS damages myelin, the fatty protective coating that surrounds nerve fibers in the brain and spinal cord. As this insulation breaks down, patients can develop neurological problems such as difficulty walking or vision impairment.

The disease does not follow the same path in everyone. Some individuals experience relatively mild symptoms for many years, while others develop serious disability and paralysis at a young age. Understanding why these outcomes differ has been a longstanding goal for researchers.

To investigate, the team focused on microglia, specialized immune cells in the brain that remove debris and support tissue repair. In patients with MS, however, these cells can undergo dramatic changes. They become filled with fat droplets, giving them a distinctive foamy appearance. Scientists refer to them as "foamy microglia."

"We found that patients with large numbers of these foamy microglia had a more severe disease course more frequently," says researcher Daan van der Vliet.

When Brain Cleanup Cells Become Overloaded

Normally, microglia help maintain brain health by clearing away damaged material. In MS, researchers believe that these cells may take in so much damaged myelin that they eventually exceed their capacity to process it.

"These cells are probably trying to do something good: clearing up damage," Van der Vliet explains. "But they become overloaded, so to speak. As a result, they can no longer effectively contribute to repair."

The study also revealed important molecular differences between MS lesions containing foamy microglia and those without them. Areas containing these cells were enriched with specific fats linked to long lasting inflammatory activity.

A More Complex View of Multiple Sclerosis

Inflammation has long been considered a major force driving MS progression. However, the new findings suggest the disease may involve a more complicated chain of events.

"It does not appear to be simply about the inflammatory response alone," says Van der Vliet. "These cells are probably attempting to clear damage and promote repair, but that process fails, worsens inflammation, and counteracts recovery."

According to the researchers, the results highlight how a mechanism that initially aims to protect the brain may eventually contribute to ongoing damage when it stops functioning properly.

Advanced Analysis of Human Brain Tissue

The research team analyzed brain tissue from 28 deceased MS patients who had donated their brains to the Netherlands Brain Bank.

Using several advanced techniques at the same time, the scientists examined gene activity, proteins, and fats within individual MS lesions. This approach allowed them to build a detailed picture of the biological processes occurring in affected brain regions.

Van der Vliet says that combining cutting edge technology with extensive knowledge of brain pathology was essential to the project's success.

"Today we have incredibly sophisticated techniques that can map the brain in great detail," Van der Vliet says. "The technologies are fantastic, but they tell you relatively little if you cannot connect them to pathology in brain tissue. Precisely because brain tissue has been carefully studied and classified for years by the Netherlands Brain Bank, we were able to recognize these abnormal patterns."

Potential Biomarkers and Personalized MS Treatment

The discovery could eventually help doctors better predict how MS will progress in individual patients.

Researchers found evidence that certain fats associated with foamy microglia may also be detectable in cerebrospinal fluid. If confirmed in future studies, these molecules could serve as biomarkers that identify patients at higher risk of rapid disease progression.

"That opens the possibility of developing biomarkers in the future that could help doctors identify earlier which patients are at risk of rapid decline -- and which treatment would suit them best."

The findings also fit with ongoing efforts to develop therapies that target fat metabolism and the expansion of chronic MS lesions. Several of these experimental treatments are already being evaluated in clinical studies conducted in collaboration with Roche.

The research was supported by two Gravitation programs: the Institute for Chemical Immunology (ICI) and the Institute for Chemical NeuroScience (iCNS).