Researchers led by Daan van der Vliet, in collaboration with teams from the Netherlands Institute for Neuroscience, Leiden University and Utrecht University, have identified a biological process that may help explain why multiple sclerosis (MS) is particularly severe in some patients. Examination of brain tissue from patients with rapidly progressing MS found large numbers of abnormal immune cells filled with lipid droplets. The findings could point to new treatment strategies and future biomarkers that help predict how quickly the disease worsens.
MS damages myelin, the protective fatty membrane that surrounds nerve fibers in the brain and spinal cord. When this insulation breaks down, patients can develop neurological problems such as difficulty walking and blurred vision.
This disease does not follow the same course in everyone. Some people experience relatively mild symptoms for many years, while others develop severe disability or paralysis at a young age. Understanding why these results differ has been a long-standing goal for researchers.
The research team focused on microglia, specialized immune cells in the brain that clear debris and support tissue repair. However, in MS patients, these cells can undergo dramatic changes. It is filled with lipid droplets, giving it a distinctive foamy appearance. Scientists call them “foamy microglia.”
“We found that patients with large numbers of these foamy microglia were more likely to have a more severe disease course,” said researcher Daan van der Vliet.
When the brain’s cleanup cells become overloaded
Normally, microglia help maintain brain health by removing damaged material. In MS, researchers believe that these cells may take up large amounts of damaged myelin, eventually exceeding the myelin’s capacity to handle it.
“These cells are probably trying to do something good by repairing the damage,” van der Vliet explains. “But it becomes overloaded, so to speak. As a result, it is no longer able to contribute effectively to the repair.”
This study also revealed important molecular differences between MS lesions that contain and do not contain foamy microglia. The areas containing these cells were enriched in certain fats that are associated with long-term inflammatory activity.
A more complex view of multiple sclerosis
Inflammation has long been thought to be a major factor promoting the progression of MS. However, new findings suggest that the disease may involve a more complex series of events.
“It doesn’t seem to be just an inflammatory response,” Dr. van der Vliet says. “These cells are likely trying to remove the damage and promote repair, but that process fails, worsening inflammation and impeding recovery.”
The researchers say the results highlight how mechanisms originally intended to protect the brain can ultimately contribute to ongoing damage when the brain no longer functions properly.
Advanced analysis of human brain tissue
The research team analyzed brain tissue from 28 deceased MS patients who donated their brains to the Dutch Brain Bank.
The scientists used several advanced techniques simultaneously to examine gene activity, proteins, and fats within individual MS lesions. This approach allowed us to build a detailed picture of the biological processes occurring in the 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.
“We now have incredibly sophisticated technology that allows us to map the brain in great detail,” van der Vliet says. “These techniques are great, but they tell us little if we can’t link them to the pathology of the brain tissue. We were able to recognize these unusual patterns only because the brain tissue has been carefully studied and categorized over many years by the Dutch Brain Bank.”
Potential biomarkers and personalized MS treatment
This discovery could ultimately help doctors more accurately predict how MS will progress in individual patients.
Researchers have found evidence that certain fats associated with foamy microglia may also be detectable in cerebrospinal fluid. If future studies identify these molecules, they could serve as biomarkers to identify patients at high risk for rapid disease progression.
“This opens up the possibility that in the future, biomarkers will be developed to help doctors identify early on which patients are at risk of rapid deterioration and which treatments are most appropriate.”
This finding is consistent with ongoing efforts to develop treatments that target fat metabolism and the spread of chronic MS lesions. Some of these experimental treatments have already been evaluated in clinical studies conducted in collaboration with Roche.
This research was supported by two gravity programs: the Institute of Chemical Immunology (ICI) and the Institute of Chemical Neuroscience (iCNS).
