Multiple sclerosis (MS) is notoriously difficult to predict. One patient might manage a relapsing-remitting course for decades with minimal disability, while another experiences rapid progression and severe neurological decline. For years, scientists have tried to categorize these differences using clinical labels like "primary progressive" or "secondary progressive," but these labels often fail to capture the underlying biology driving the disease in an individual brain. A groundbreaking new study from the Netherlands Brain Bank has taken a different approach. Instead of relying on clinical symptoms observed during life, researchers analyzed the brains of 226 MS donors after death, using advanced statistical modeling to find hidden patterns in the chaos. By "disentangling" this data, they identified three distinct neuropathological "dimensions" that explain why MS looks so different from person to person.
Dimension 1: The Aggressive Driver of Progression
The first dimension identified by the researchers paints a picture of MS at its most destructive. Donors who scored high on this dimension displayed a "perfect storm" of pathology: a high number of active lesions, extensive neuroaxonal damage, and a specific type of immune cell known as "foamy microglia". This dimension was strongly linked to the presence of B and T cells in the brain, suggesting an active, ongoing battle by the adaptive immune system. Clinically, this pattern translated to a much more severe disease course. Patients with this profile progressed to needing walking aids significantly faster and passed away at a younger age. This dimension likely represents the biological engine of "progression"—the active, inflammatory demyelination that drives rapid disability.
Dimension 2: The Genetic Spark and Lesion Initiation
The second dimension revealed a fascinating paradox regarding the genetics of MS. High scores here were associated with the presence of "nodules" and active lesions populated by ramified (bushy) microglia, rather than the destructive foamy kind seen in Dimension 1. What makes this dimension unique is its strong connection to genetics: it correlates with the presence of HLA-DRB1*15:01, the strongest known genetic risk factor for developing MS. However, contrary to what one might expect, donors who scored high on this "genetic risk" dimension actually had less severe disease and lived longer. This suggests that while these genetic factors might trigger the onset of MS (lesion initiation), they do not necessarily drive the severity or progression of the disability once the disease has started.
Dimension 3: The Slow Burn and Scar Formation
The third dimension appears to represent the "aftermath" or a chronic, smoldering phase of the disease. This pattern was defined by inactive lesions and scar formation, with less involvement from the adaptive immune system (fewer B and T cells). Patients scoring high on this dimension typically had a much longer disease duration, surviving for many years with the condition. Interestingly, while this dimension was associated with less axonal damage overall, it was specifically linked to subpial cortical lesions—damage occurring on the surface of the brain. This finding aligns with the idea that as inflammation "burns out" over decades, the disease settles into a state characterized by scarring and specific grey matter pathology, distinct from the aggressive destruction seen in early or progressive stages.
Rethinking Clinical Labels: Biology Over Symptoms
One of the most critical takeaways from this research is that these three biological dimensions cut across the traditional clinical categories we use today. The study found no significant correlation between these neuropathological patterns and the standard labels of Relapsing-Remitting, Secondary Progressive, or Primary Progressive MS. This confirms a growing suspicion in the scientific community: traditional clinical phenotypes are artificial boundaries that don't reflect the true biological diversity of the disease. A patient diagnosed with "Progressive MS" might biologically have more in common with the "Dimension 1" profile of active inflammation than with the "Dimension 3" profile of scarring, or vice versa. This mismatch explains why treatments that work for one "progressive" patient might fail completely for another.
The Role of Microglia: It’s Not Just About "Active" or "Inactive"
This study also forces us to upgrade our understanding of the brain's immune cells, the microglia. Previously, lesions were often just categorized as active or inactive. However, this data shows that how the microglia behave matters immensely. "Foamy" microglia were the hallmark of the severe, destructive Dimension 1, associated with acute axonal stress and rapid decline. In contrast, "ramified" microglia were associated with Dimensions 2 and 3, which correlated with milder disease or longer survival. This nuance is vital for future drug development; simply "suppressing" microglia might not be the answer. Instead, therapies may need to target specific microglial states—calming the destructive "foamy" response while perhaps preserving the functions associated with the ramified morphology.
Toward Precision Medicine for MS
Ultimately, this "disentanglement" of MS pathology opens the door to genuine precision medicine. By understanding that a patient’s disease is composed of independent dimensions—immune-driven demyelination (Dim 1), genetically influenced initiation (Dim 2), and chronic scarring (Dim 3)—we can start to envision treatments tailored to the specific biological driver active in a patient. For instance, patients scoring high on Dimension 1 might benefit most from aggressive anti-inflammatory therapies or BTK inhibitors that target B cells and microglia. Meanwhile, those with a Dimension 3 profile might require neuroprotective strategies focused on cortical preservation. These findings move us a step closer to treating the biology of the patient, rather than just the symptoms of the disease.
Disclaimer: This blog post is based on the information provided in the cited scientific article. It aims to provide an accessible summary of the research findings and should not be considered as definitive medical advice. For any health concerns, please consult with a qualified healthcare professional.
Reference:
de Boer, A., van den Bosch, A.M.R., Mekkes, N.J. et al. Disentangling the heterogeneity of multiple sclerosis through identification of independent neuropathological dimensions. Acta Neuropathol 147, 90 (2024). https://doi.org/10.1007/s00401-024-02742-w