Brain Iron Levels a New Marker of MS Progression?

July 20, 2018

Monitoring levels of iron in specific areas of the brain in patients with multiple sclerosis (MS) by using novel MRI may track disease progression and assess treatment efficacy in clinical trials, new research suggests.

The study shows that the new technique, known as quantitative susceptibility mapping (QSM), identified different iron patterns in the brains of patients with MS compared with healthy controls.

Specifically, patients with MS had lower iron content in the thalamus and higher iron content in other deep gray-matter structures compared with controls. In addition, the extent of these changes was associated with longer disease duration, higher disability degree, and disease progression.

Lead investigator Robert Zivadinov, MD, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, New York, believes monitoring iron levels in this way could complement brain atrophy as a measure of MS progression and also lead to earlier diagnosis.

"Previously it has been found that MS patients have a higher iron content in several gray-matter brain structures, although iron seem to be lower in the white matter. However, iron levels in the thalamus — part of the gray matter and one of the earliest affected areas of the brain in MS — are not clear," he told Medscape Medical News.

"We found that iron levels are significantly lower in the thalamus in patients with MS compared with healthy controls. And patients with progressive forms of MS had lower levels than those with relapsing-remitting MS or clinically isolated syndrome," he added.

The study was published online July 17 in Radiology.

Independent Predictor of Disability

The researchers hypothesize that lower iron levels in the thalamus may be due to the death of iron-rich oligodendrocytes in patients with MS.

For the study they performed the QSM mapping technique on 600 patients with MS, including 452 with early-stage disease and 148 whose disease had progressed.

Compared with 250 healthy controls, patients with MS had higher levels of iron in the basal ganglia, a group of structures central to movement. However, the patients with MS had lower levels of iron in the thalamus.

These changes were associated with clinical disability and persisted even after adjustment for changes in the brain volumes of each individual structure.

"In this large cohort of MS patients and healthy controls, we have reported, for the first time, iron increasing in the basal ganglia but decreasing in thalamic structures. Our results how that iron depletion or increase in several structures of the brain is an independent predictor of disability related to MS," Zivadinov said.


The researchers also adjusted the results for brain atrophy and found that lower iron levels in the thalamus were associated with progression of disease and levels of disability independent of brain atrophy.

"So brain atrophy appears to be just one part of the story. Lack of iron in key brain structures may be another key part of the pathological process underlying MS," said Zivadinov.

The findings also suggest that QSM is very sensitive to brain iron levels. Because blood is iron rich, the technology is currently used to detect brain hemorrhage.

However, said Zivadinov, these new findings suggest QSM may also be a "potential new way of monitoring MS disease progression and in the assessment of new therapies in clinical trials."

Current treatments involving anti-inflammatory drugs do not prevent patients with MS from developing disability, he noted.

"To be able to act against changes with this technique would be extremely beneficial," he said.  The next step will be to conduct longitudinal studies to assess how brain iron levels change over time."

Relevance Still a Question

In an accompanying editorial, Frederik Barkhof, MD, VU University Medical Center, Amsterdam, the Netherlands, and  David L. Thomas, PhD, UCL Institute of Neurology, London, United Kingdom, explain that the mechanisms of disability progression in MS are not completely understood.

They point out that damage to the gray matter is of special interest and that QSM represents a new MRI measure to determine damage to these deep gray-matter regions.

These findings, the editorialists note, "confirm in a large sample that abnormal deep gray matter iron content impacts disease evolution of multiple sclerosis and disability accrual" and "highlight the potential of quantitative susceptibility mapping as a biomarker of neurodegenerative disease."

However, the question of whether iron deposition in MS outperforms other MRI measures of neurodegeneration remains.

Noting that iron is an important element in metabolic pathways that has both beneficial and detrimental effects in the central nervous system, they conclude that "iron accumulation in the thalamus seems to have clinical relevance beyond simple measures of atrophy" but that "more work is needed to understand the value of quantitative susceptibility mapping for determining patient prognosis and monitoring treatment in multiple sclerosis."

This study was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health. Zivadinov, Barkhof, and Thomas have disclosed no relevant financial relationships.  

Radiology. Published online July 17. Full text, Editorial

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