Subtle Brain Changes May Drive Disability in Multiple Sclerosis Beyond Visible Lesions

For decades, multiple sclerosis (MS) research has focused largely on the inflammatory lesions visible on MRI scans. Yet new evidence suggests that changes in normal-appearing white matter (NAWM) and normal-appearing gray matter (NAGM) may play an equally important role in driving long-term disability.¹

The review published in Acta Neuropathologica synthesized findings from recent neuropathology and imaging studies, concluding that diffuse alterations in tissue that looks unaffected on routine scans represent a “clinically relevant, pathological entity distinct from demyelinating lesions.”

Lesions occur in both the white matter and gray matter of the brain and spinal cord, but they differ in their microscopic features and timing of development.² Tissue studies show that multiple immune cell types are present within these lesions, indicating that MS-related damage is partly caused by immune cells from outside the central nervous system ( b) that infiltrate and attack myelinated axons. However, the authors argued that focusing solely on lesion counts underestimates the true burden of disease.¹

People with MS often experience progression of disability even in the absence of new lesions detected using MRI. This disconnect has led researchers to investigate what occurs in brain tissue that appears normal using conventional imaging. Evidence now indicates that subtle changes in myelin integrity, immune cell function, neuronal connectivity, and energy metabolism accumulate over time in NAWM and NAGM, contributing to symptoms such as fatigue, cognitive decline, and motor dysfunction.

The authors conducted a targeted literature review of publications indexed in PubMed through March 2025, with emphasis on studies from the last decade. They examined pathology, molecular biology, and neuroimaging evidence on structural and functional changes in NAWM and NAGM. Although not a systematic review, the review integrated findings across diverse methodologies, from single-cell sequencing to diffusion MRI.

They highlighted several recurring themes:

• Myelin abnormalities: Even in the absence of overt lesions, NAWM showed subtle myelin loss, altered lipid composition, and structural defects such as decompaction and blistering. Some repair mechanisms were active, with evidence of remyelination in subsets of patients, though success varied
• Oligodendrocyte and microglia dysfunction: Oligodendrocytes in NAWM appeared skewed toward stress responses, while microglia lost their normal regional specificity and displayed hyperreactivity. Microglial “nodules” enriched for MS susceptibility genes and lipid dysregulation were observed in NAWM, suggesting focal zones of smoldering pathology
• Axonal and synaptic injury: Axonal degeneration occurred in both NAWM and NAGM, sometimes independent of visible lesion burden. In frontal cortical regions, axonal loss reached up to 33% compared with control tissue. Synapse loss in NAGM was widespread, affecting both excitatory and inhibitory connections, and often preceded demyelination
• Aging interactions: Glial cells in NAWM exhibited accelerated epigenetic aging compared with healthy controls, indicating that age-related changes may synergize with MS pathology to worsen outcomes

Together, these processes suggest that “alterations in normal-appearing tissue may not only give rise to overt lesions, but also underlie disability accumulation from the earliest stages of disease, which manifest once repair mechanisms are exhausted,” the authors wrote.

The underlying studies included in the review drew from diverse MS populations. Postmortem tissue samples came from individuals with relapsing-remitting, secondary progressive, and primary progressive MS, spanning early to advanced disease stages. Imaging studies also included people with clinically isolated syndrome and long-standing MS, allowing comparisons across disease trajectories.

The authors acknowledged several limitations. The literature search was not systematic, raising the possibility of selection bias. Many studies had small sample sizes, reflecting the challenge of obtaining high-quality postmortem brain tissue. Additionally, results across cohorts were sometimes inconsistent, particularly regarding the extent of neuronal loss in NAGM. Bulk tissue analyses also limited the ability to assign molecular changes specifically to myelin or glial cell subtypes.

The findings support a shift away from a lesion-centric model of MS. The recognition that “normal-appearing” tissue harbors diffuse, clinically relevant pathology underscores the need for therapies that go beyond reducing acute inflammatory lesions. Interventions targeting myelin repair, microglial regulation, and neuroprotection may help slow disability progression, particularly in progressive forms of MS.

As the authors concluded, “A wider understanding of the pathophysiology of the ‘normal-appearing’ MS tissue not only provides a more complete picture of disease progression, but also emphasizes the need for therapeutic approaches targeting such diffuse prelesional changes to slow or halt disability accumulation in MS.”

References

1. González GM, Hart BAT, Bugiani M, et al. A focus on the normal-appearing white and gray matter within the multiple sclerosis brain: a link to smoldering progression. Acta Neuropathol. 2025;150(1):16. doi:10.1007/s00401-025-02923-1

2. Hauser SL, Cree BAC. Treatment of multiple sclerosis: a review. Am J Med. 2020;133(12):1380-1390.e2. doi:10.1016/j.amjmed.2020.05.049