Summary: Multiple sclerosis (MS) is notoriously unpredictable. While some individuals remain clinically stable for decades, others suffer a rapid, aggressive progression of neurological disability. Historically, clinically predicting these divergent paths has been an immense challenge for neuroimmunologists.
To map the biological architecture behind this variability, researchers conducted a landmark study combining pathological, clinical, and genetic data from 287 MS brain donors through the Netherlands Brain Bank. Representing the largest well-characterised MS pathology cohort available globally, researchers systematically analyzed the tissue for distinct patterns of damage and repair.
The study proves that MS is not a uniform disease process; rather, unique combinations of blood-vessel inflammation, deep immune cell clusters, broad rim lesions, and variable myelin repair capabilities dictate an individual’s disease trajectory, and these distinct sub-types are heavily shaped by a patient’s genetic profile.
Key Facts
- The Paradigm of Plurality: The study reinforces that MS operates as a collection of distinct sub-processes rather than a singular disease track, with different inflammatory and repair mechanisms dominating in different individuals.
- The Four Pathological Pillars: Researchers concentrated on four critical tissue metrics: perivascular inflammation (inflammation around blood vessels), parenchymal immune cell clusters, the presence of chronic active “broad rim” lesions, and endogenous remyelination (myelin repair capacity).
- The Broad Rim Penalty: The presence of broad rim lesions served as a robust structural predictor for the most severe, fast-tracking clinical disease courses.
- The Myelin Repair Deficit: A low capacity for remyelination directly correlated with widespread, chronic, irreversible brain tissue damage rather than acute flare-ups.
- Genetic Mapping of Inflammation: Patients carrying specific genetic variants known to elevate overall MS risk displayed significantly higher rates of perivascular inflammation and immune cell clustering, directly linking host genetics to the brain’s internal inflammatory behavior.
- Progression Gene Linked to Rim Lesions: A specific genetic variant previously identified in clinical literature as a driver of accelerated MS progression was found tightly correlated with the structural development of broad rim lesions.
- The Hunt for Live Biomarkers: While this postmortem study is fundamental science, it sets up the next translational milestone: developing high-resolution imaging or fluid biomarkers capable of identifying these specific tissue matrices in living patients to unlock personalized, precision neuroimmunology treatments.
Source: KNAW
Why does multiple sclerosis progress quickly in some people, while others remain stable for years? Researchers from the Netherlands Institute for Neuroscience have identified biological patterns in the brain that may help explain these differences. Their study shows that these patterns are linked to disease severity and are partly shaped by genetics.
In a new publication, first authors Lukas Lutje and Alida Chen from the Huitinga group analysed pathological, clinical, and genetic data from 287 people with MS who donated their brain to the Netherlands Brain Bank. It is the largest well-characterised MS pathology cohort currently available.
The researchers examined whether people with MS show distinct patterns of brain damage and repair. They focused on four pathological characteristics: inflammation around blood vessels, clusters of immune cells in the brain, the presence of broad rim lesions, and the brain’s ability to repair myelin—the protective coating around nerve fibres.
“MS is not one single disease process,” says Aletta van den Bosch. “Different inflammatory and repair mechanisms dominate in different people, helping explain why the disease can follow very different paths.”
Finding patterns
The team found that these four pathological characteristics were associated with different patterns of lesion activity, tissue repair, and disease severity. For example, people with broad rim lesions were more likely to have a more severe disease course, while those with poor capacity for myelin repair had more chronic tissue damage.
Genetic variants known to increase the risk of developing MS were more common in people with inflammation around blood vessels and clusters of the brain’s immune cells, suggesting that genetic background contributes to the inflammatory processes occurring in the brain. Another genetic variant, previously associated with faster disease progression, was more frequently observed in people with broad rim lesions.
By combining pathology, genetics and clinical information, the researchers were able to identify donor-specific pathological features that help explain why MS differs so much between individuals
Although this is fundamental research, it provides a basis for understanding why MS differs so much between individuals. The next step is to find biomarkers that can detect these biological patterns in people living with MS. Such biomarkers could help monitor disease processes over time and ultimately support more personalised treatment strategies.
“Understanding which biological processes are driving disease in each individual will be key to developing more personalised treatments,” the researchers conclude.
Key Questions Answered:
A: For a long time, multiple sclerosis was treated clinically as a single disease process that just happened to hit people differently. This study turns that theory on its head. By evaluating 287 donor brains, the Netherlands Institute for Neuroscience team proved that MS is actually a collection of distinct biological sub-processes. In one patient, the disease might be heavily driven by aggressive, smoldering edge lesions, while in another, it is characterized by a failure to repair basic nerve coatings. Which of these sub-mechanisms dominates inside your brain determines whether your clinical course is mild or aggressive.
A: A broad rim lesion, often referred to in clinical imaging as a iron-rim lesion—is a type of chronic, active damage spot in the brain. Instead of flaring up and cooling down like a standard MS lesion, a broad rim lesion features a highly active, smoldering outer border packed with destructive immune cells. This ring slowly but continuously expands outward, eating away at surrounding healthy tissue over years. The study confirmed that donors who possessed these specific rim lesions were the exact individuals who experienced the fastest, most severe progression of physical and cognitive disability during their lives.
A: The study revealed a direct genetic line to brain pathology. The researchers found that donors who carried common genetic variants linked to the general risk of getting MS had brains defined by intense inflammation around blood vessels and heavy clustering of immune cells. More importantly, they discovered that a completely separate genetic variant, one previously known to cause faster disease progression—was found almost exclusively in patients who developed dangerous broad rim lesions. This proves that your unique genetic background actively programs how your immune system attacks your brain, writing the script for your specific disease path.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this multiple sclerosis research news
Author: Eline Feenstra
Source: KNAW
Contact: Eline Feenstra – KNAW
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Donor-specific pathological features associate with genetic background, lesion type distribution, and clinical heterogeneity in multiple sclerosis” by Lukas Lütje, J. Q. Alida Chen, Jörg Hamann, Joost Smolders, Inge Huitinga & Aletta M. R. van den Bosch. Acta Neuropathologica
DOI:10.1007/s00401-026-03040-3
Abstract
Donor-specific pathological features associate with genetic background, lesion type distribution, and clinical heterogeneity in multiple sclerosis
Multiple sclerosis (MS) shows pronounced pathological and clinical variability between individuals, reflecting differences in genetic susceptibility, inflammatory activity, and tissue repair. This variability complicates efforts to relate lesion pathology to clinical trajectories.
In previous work in the Netherlands Brain Bank MS autopsy cohort (NBB-MS), we showed that relative proportions of different lesion types, lesion load, and microglia/macrophage activity score, associate with clinical severity, while also revealing marked inter-individual variability.
Here, we extend these observations by examining whether selected donor-specific pathological features relate to genetic background, quantitative lesion type distributions, and clinical disease course, and thereby help contextualize this heterogeneity.
