Multiple sclerosis lesion patterns tied to donor genetics and clinical diversity

In one of the largest neuropathological studies of multiple sclerosis ever undertaken, researchers examining autopsy brain tissue from 287 donors have uncovered compelling evidence that the disease leaves deeply personal fingerprints in the central nervous system—fingerprints that can be traced back to a person’s genetic makeup and forward to the clinical course they experienced in life. The study, published in Acta Neuropathologica, draws on the Netherlands Brain Bank MS autopsy cohort (NBB-MS) and reveals that four distinct pathological features—perivascular cuffs, microglial nodules, broad rim lesions, and remyelination efficiency—are not random quirks of individual cases, but biologically meaningful markers that link genetic risk, lesion patterns, and clinical severity into a coherent picture of why multiple sclerosis manifests so differently from one patient to the next.

Multiple sclerosis has long been recognized as a disease of extraordinary variability. Some patients lose the ability to walk within a decade of diagnosis, while others remain ambulant for decades. Under the microscope, the variability is just as striking: some brains are riddled with actively inflamed demyelinated lesions, while others show mostly burned-out, inactive scars. For years, this heterogeneity has frustrated efforts to draw clean lines between what pathologists see in post-mortem tissue and what clinicians observed in the patient while alive. The new research argues that the missing link may lie in donor-specific pathological features—persistent, recurring characteristics of an individual’s inflammatory and reparative biology that color everything the disease does in that person’s brain.

The research team, led by Lukas Lütje and J. Q. Alida Chen along with colleagues including Jörg Hamann, Joost Smolders, Inge Huitinga, and Aletta M. R. van den Bosch, systematically assessed brain tissue from 287 donors with confirmed MS pathology, collected between 1990 and 2021. The scale of the sampling effort is remarkable: on average, nearly 22 tissue blocks and more than 35 lesions were dissected per donor, taken from standardized locations in the brainstem, with lesions identified macroscopically or guided by post-mortem magnetic resonance imaging. Each tissue block was formalin-fixed and paraffin-embedded, then subjected to double immunostaining for human leukocyte antigen proteins (HLA-DP-DR-DQ) and proteolipid protein (PLP)—a technique that simultaneously reveals activated microglia and macrophages, the inflammatory workhorses of the disease, and the myelin they attack. Iron deposition was visualized using a DAB-enhanced Turnbull Blue staining method, adding another layer of pathological detail.

The four donor-specific features at the heart of the study each capture a different dimension of MS biology. Perivascular cuffs are exaggerated accumulations of lymphocytes—both B and T cells—crowding into the perivascular spaces of the brain, visible when at least one such space shows the hallmark buildup in any examined tissue block. Microglial nodules are small clusters of at least four ramified microglia, the brain’s resident immune cells, appearing in tissue that otherwise looks normal—the so-called normal-appearing white matter. Broad rim lesions, or BRLs, are a particularly dramatic subtype of chronic active lesion, defined by a hypercellular HLA-positive rim at least one millimeter wide surrounding a hypocellular, fully demyelinated core. And remyelination efficiency divides donors into efficient remyelinating donors and poorly remyelinating donors, based on the proportion of lesions showing repair, with a threshold set at a remyelinated lesion proportion of at least 0.27.

When the researchers crossed these pathological features with the donors’ genetic profiles, striking associations emerged. Carriers of the HLA-DRB115:01 allele—by far the strongest known genetic risk factor for multiple sclerosis, tagged by the SNP rs3135388—showed a higher prevalence of both perivascular cuffs and microglial nodules. This finding is biologically provocative: HLA-DRB115:01 encodes a molecule that presents antigens to T cells, and its association with lymphocytic cuffing suggests that the classic genetic gateway to MS risk may shape the very character of the inflammatory infiltrates in the brain decades later. Meanwhile, carriers of a severity-associated variant in the DYSF–ZNF638 locus (rs10191329), which prior genome-wide studies have linked to faster disability progression, showed enrichment of both broad rim lesions and perivascular cuffs—hinting that genetic determinants of severity may act partly by promoting more aggressive, more heavily inflamed lesion architectures.

The clinical correlations were equally revealing. Perivascular cuffs were associated with an increased microglia/macrophage activation score across the brain and with a younger age at death, suggesting that donors whose brains harbored these lymphocyte accumulations died earlier and with more widespread innate immune activation. Microglial nodules in the normal-appearing white matter—the tissue that appears spared at first glance—were associated with a higher proportion of actively inflamed lesions elsewhere, implying that these subtle clusters of immune cells may be a harbinger of a brain in which inflammatory lesion formation remains in full swing. The presence of these nodules may thus serve as an indicator of ongoing, brain-wide inflammatory activity even in regions that would never be flagged as lesions on conventional examination.

Broad rim lesions carried perhaps the weightiest clinical associations of all. Donors with BRLs showed increased proportions of both active and mixed active/inactive lesions, a higher lesion rate in the brainstem, and—a crucial finding—a higher age-related Multiple Sclerosis Severity Score, a metric that adjusts disability for age to capture how aggressively the disease has progressed. The broad rim itself is thought to represent a smoldering zone of myelin-phagocytosing macrophages at the lesion edge, and the new data reinforce the idea that these structures are engines of ongoing damage rather than passive scars. The association with brainstem lesions is particularly notable, as brainstem involvement often correlates with severe, disabling disease courses.

On the repair side of the ledger, poor remyelination efficiency painted its own distinctive portrait. Donors classified as poorly remyelinating showed a higher proportion of mixed active/inactive and inactive lesions and, tellingly, a shorter disease duration. The link with shorter disease duration is intriguing and suggests that inefficient repair may accelerate the trajectory toward severe disability and death, compressing the disease course. It may also reflect a vicious cycle in which active inflammation impairs oligodendrocyte precursor cells’ ability to rebuild myelin sheaths, leaving lesions unrepaired and vulnerable axons exposed to further injury. The loss of the protective, insulating myelin sheath ultimately leads to neurodegeneration, and the study’s authors and their predecessors have consistently shown that inflammatory lesion activity persists until death and correlates closely with that neurodegeneration.

The lesion classification system underpinning the work is itself a technical achievement. Lesions in white matter and deep grey matter were categorized by integrating innate inflammatory activity, assessed through HLA staining, with myelin status assessed by PLP staining. Reactive sites—aggregates of microglia and macrophages without demyelination—were distinguished from active lesions with dense microglial accumulation and partial myelin loss, mixed lesions with a rim of myeloid cells surrounding a quiescent core, inactive hypocellular lesions, and remyelinated lesions showing sparse inflammation and partial myelination restoration. Cortical lesions were classified by anatomical location as leukocortical, intracortical, or subpial. Against this standardized backdrop, the donor-specific features stand out as modifiers—variables that reshape the statistical landscape of lesion types and clinical outcomes rather than merely adding noise.

What makes this study transformative is its implication for how post-mortem MS research is conducted and interpreted. Rather than treating all donors with MS as members of a single pathological population, the findings argue for a stratified approach in which cuff status, nodule status, BRL presence, and remyelination efficiency are recorded alongside lesion classifications. Two donors with identical lesion loads could, in this framework, represent fundamentally different biological states—one with brisk lymphocyte-driven inflammation tied to HLA risk alleles, the other with smoldering broad-rimmed lesions tied to severity loci and a failing repair program. Pooling such donors in a typical case-control analysis would wash out precisely the signals that matter most for understanding disease mechanisms and for designing targeted therapies.

The work also resonates with the broader movement in MS research toward recognizing the disease as a spectrum of interacting pathological dimensions rather than a single entity. Prior analyses from the same cohort demonstrated that lesion load, the proportion of mixed active/inactive lesions, and microglial activation scores associate with clinical severity while also varying enormously between individuals. By showing that this inter-individual variability has genetic roots and clinical consequences, the new study closes the loop: it connects the genome to the lesion microenvironment to the bedside. Patients carrying risk or severity alleles may be pre-programmed, in a sense, to build different kinds of lesions and to repair them differently, with predictable consequences for how their disease unfolds.

For the estimated 2.9 million people worldwide living with multiple sclerosis, the clinical translation of such findings remains on the horizon rather than at hand—autopsy tissue, by definition, comes from those who have died, and the features studied here cannot yet be visualized reliably in living patients. But the biological logic they reveal is actionable. Therapies aimed at enhancing remyelination, for example, may need to be tailored differently for patients whose reparative capacity is genetically or immunologically compromised, while anti-inflammatory strategies might be stratified by whether a patient’s pathology is dominated by lymphocytic cuffing or by smoldering myeloid rims. Biomarker development, too, could take cues from these pathological dimensions, seeking surrogate markers in blood or advanced imaging that recapitulate what the microscope sees.

In the end, the study’s message is one of biological individuality made rigorous. The 287 donors of the Netherlands Brain Bank, through their extraordinary gift, have shown that multiple sclerosis is not one disease stamped identically upon every brain it touches, but a process profoundly shaped by each person’s genetic inheritance and intrinsic inflammatory and reparative character. Reading those individual signatures in the tissue—and understanding how they link risk variants, lesion architecture, and clinical fate—may finally provide the framework needed to explain, and one day to predict, why this disease takes such different courses in different lives.