Study finds MRI-detected myelin changes tied to disability in RRMS

A specialized MRI technique detected signs of myelin and iron loss in nerve fibers beneath the brain’s outer layer in people with relapsing-remitting multiple sclerosis (RRMS), but not in those with a related disease, called neuromyelitis optica spectrum disorder (NMOSD).

That’s according to a study in China that also found that, among people with RRMS, myelin-related changes in these nerve fibers, called U-fibers, were linked to disability scores and lesion burden.

“In RRMS patients, this technique revealed underlying [disease-associated] changes in the U-fiber region, characterized by iron reduction and demyelination [myelin loss], which were not observed in NMOSD patients,” the researchers wrote.

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Overall, the findings suggest that the technique may help researchers better understand RRMS-associated brain damage and provide an imaging marker linked to disability. However, it did not reliably distinguish people with RRMS from those with NMOSD after factors such as disease severity and lesion burden were taken into account.

The study, “Comparison of iron and myelin changes in U‑fiber regions of relapsing–remitting multiple sclerosis and neuromyelitis optica spectrum disorders,” was published in the Journal of Neurology.

MS is an inflammatory disease of the brain and spinal cord marked by abnormal immune attacks against the myelin sheath, the protective coating around nerve fibers. This damage can lead to hallmark lesions, or areas of damage, primarily in the brain’s white matter, which is made up largely of nerve fibers, and can cause symptoms.

Similarly, NMOSD is an inflammatory disease that primarily affects the spinal cord and optic nerves, which carry visual signals between the eyes and the brain. It is often confused with MS because the two diseases can have overlapping symptoms and similar-looking lesions. Unlike MS, abnormal immune attacks in NMOSD primarily target astrocytes, a type of nerve-supporting cell.

U-fibers are short, U-shaped myelinated nerve fibers located in the brain’s superficial white matter, just beneath the brain’s outer layer, or cortex. They connect neighboring areas of the cortex.

Research suggests that U-fibers are more sensitive to damage because of their thinner axons and thinner myelin sheaths. In addition, this U-fiber region naturally contains higher iron concentrations than deeper white matter regions, so changes in iron levels may indicate underlying pathological changes.

Researchers compare U-fiber changes in RRMS and NMOSD

With this in mind, scientists in China investigated myelin and iron differences in U‑fiber regions between RRMS and NMOSD patients using a specialized MRI technique called susceptibility separation imaging.

The technique separates MRI signals that are mainly associated with iron from those associated with myelin. These are indirect imaging markers rather than direct measurements of iron or myelin.

The study included 119 adults with RRMS, 47 with NMOSD who tested positive for AQP4-IgG, the most common NMOSD-driving antibody, and 93 healthy individuals who served as controls.

People with RRMS were less disabled than those with NMOSD, as assessed by the validated Expanded Disability Status Scale (EDSS). Still, RRMS patients had significantly larger overall and U-fiber lesion volumes than NMOSD patients, and significantly lower white matter and U-fiber volumes compared with both NMOSD patients and controls.

Across the overall normal-appearing U-fiber region, the iron-related measure did not differ among the three groups. However, RRMS patients had more myelin loss than healthy controls, a result not seen in NMOSD patients.

This finding “may be explained by the distinct [underlying mechanisms] of NMOSD, which is primarily driven by astrocyte damage … rather than primary demyelination, and, therefore, may exert limited effects on the microstructural integrity of normal-appearing U-fiber,” the researchers wrote.

Both RRMS and NMOSD patients showed significantly more myelin loss and iron loss in U-fiber lesions than in their normal-appearing U-fiber regions. However, within U-fiber lesions, RRMS patients showed significantly more myelin loss than NMOSD patients.

MRI differences fade after accounting for disease burden

These results suggested that the MRI technique might help distinguish RRMS from NMOSD. However, after the researchers accounted for age, sex, disease duration, disability, and total lesion volume, the differences between the two patient groups were no longer statistically significant.

Therefore, the utility of U-fiber susceptibility metrics in “differentiating RRMS from NMOSD may be limited, particularly when disease severity and lesion burden are taken into account,” the team wrote.

Among RRMS patients, greater myelin loss was significantly associated with higher EDSS scores, reflecting greater disability. The strongest link was found in the left superior frontal region, which includes areas involved in motor planning and coordination. Therefore, “microstructural damage to these U-fibers may disrupt the transmission of motor-related signals,” the researchers wrote.

In addition, greater U-fiber demyelination in RRMS patients was associated with larger overall brain lesion volumes and lower white matter and U-fiber volumes.

The researchers concluded that susceptibility separation imaging provided “surrogate markers suggestive of iron loss and demyelination” in the U-fiber region of RRMS patients, that these metrics were closely associated with lesion burden, and that they may hold promise as imaging correlates of clinical disability.

Further longitudinal studies are needed to track these changes over time and assess their prognostic value.