NIH Funds Study of Brain Iron in Multiple Sclerosis Progression and Remission
Does brain iron status influence multiple sclerosis (MS) progression or remission?
There is evidence, largely from the study of deceased patients, that white matter iron loss is related to MS disease progression. Yet measuring white matter iron in living patients is not possible and currently prevents the development of iron-targeted therapies. The key to understanding the impact of iron on MS may, instead, lie in the assessment of easier-to-measure gray matter iron and the cells associated with it.
The U.S. National Institute of Neurological Disorders and Stroke will invest $1.4 million in a study to explore this question. The four-year study will be led by Ferdinand Schweser, Ph.D., Director of Sequence Development at the Buffalo Neuroimaging Analysis Center (BNAC) and Associate Professor of Neurology, Radiology, and Biomedical Engineering at the University at Buffalo.
The team’s central hypothesis is that MS progression and disability worsening are linked to a global depletion of iron from the glial syncytium (a large network of interconnected non-neuronal cells in the nervous system that do not produce electrical impulses, but support and protect neurons). Further, the team hypothesizes that this depletion can be measured in the deep gray matter of living patients with a technique called quantitative susceptibility mapping (QSM).
Accordingly, clinical monitoring of glial iron status would provide a novel and complementary marker of MS. It means we could significantly improve our ability to detect disease activity in the absence of acute symptoms. Moreover, confirmation of the impact of declining glial iron will call for a paradigmatic shift in the treatment of brain iron dysregulation—from reducing iron-toxicity toward sustaining physiologically essential iron.
Improving Detection of Brain Iron and Its Relation to MS
Myelination, the fatty sheath surrounding neuronal processes and fibers, limits the effectiveness of MRI scans of white matter iron in living patients. Because myelination is less concentrated in gray matter than it is in white matter, gray matter iron is easier to measure. This advantage, coupled with the relatively high concentration of iron present in gray matter, point to the importance of learning how gray matter iron relates to MS.
The possibility of reliably measuring gray matter iron using MRI and QSM has been supported by recent BNAC research. Using QSM, BNAC researchers and others have been able to measure the magnetic susceptibility of thalamus (gray matter) tissue throughout the disease course, compared to controls. In addition, changes in the pulvinar nucleus (also gray matter) predicted clinical disability, disease subtype, and disease duration. Recent iron measurements by BNAC and others further suggested that declining iron can be measured also in other deep gray matter regions.
Despite these indications, no one has yet systematically confirmed the association of these imaging findings with disease progression. Moreover, our lack of knowledge about the cell types associated with iron hampers progress in the use of this unique imaging marker for monitoring disease progression in the clinic or in clinical trials.
The BNAC study addresses the critical need for a longitudinal study that:
- Identifies trajectories of deep gray matter iron (magnetic susceptibility) in patients and controls,
- Relates them to clinical symptoms, and
- Determines their underlying biological substrate (cell types).
These outcomes would represent a novel, potentially powerful, objective means to assess brain iron status along with confidence that it serves as part of a biomarker of MS progression and remission. Understanding the substrate—the different cell types where iron is concentrated—and how it is altered in post-mortem MS patients compared to healthy control brains, could open the door for new iron-focused therapies.
Schweser’s international team will analyze thousands of MRI scans taken over 10 years to study disease progression over the disease duration between onset and 30 years. MRIs will be from “NeuroSTREAM,” the world’s largest MRI dataset, which includes subjects who participated in prospective, IRB-approved studies at the University at Buffalo MS center since 2007. Most patients are from the Buffalo, NY area who are imaged annually in the first 15-20 years of the disease.
By determining the association between disease progression and MRI markers of brain iron homeostasis, the researchers hope to confirm whether deep gray matter iron content declines as the disease progresses. And by identifying the cellular and molecular substrate of gray matter iron in these patients, they may confirm that oligodendroglial iron export is the primary cause of reduced iron content as measured by MRI.
The study will provide the first quantitative and systematic biochemical evidence for alterations in iron homeostasis across deep gray matter regions in people with MS. The findings will have important implications for the fundamental understanding of MS pathology because they imply iron loss is a global phenomenon affecting all MS patients.
The Future
Whether or not the hypothesis is verified, the study will provide conclusive evidence of alterations in the gray matter cellular iron status in MS and the interplay between tissue iron and neurodegeneration across the whole disease duration in patients with MS. Also, with this foundation, QSM may add to the available endpoints of clinical trials evaluating neuroprotective and neuroregenerative therapies for MS.
International Collaboration
Schweser and the BNAC team are collaborating with Simon Hametner, Ph.D., Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna and Günther Grabner, Ph.D., Kärnten University of Applied Sciences, both in Austria. Other co-investigators are Robert Zivadinov, MD, Ph.D., BNAC’s Director and Professor of Neurology and Biomedical Informatics at the University at Buffalo; and Michael. G. Dwyer, Ph.D., BNAC Director of Neuroinformatics, and Associate Professor of Neurology and Biomedical Informatics at the University at Buffalo.
Building on BNAC Research
The NIH-funded research builds on other studies performed by Schweser and his colleagues at the University of Buffalo’s 21-year-old Buffalo Neuroimaging Analysis Center, led by Center Director Robert Zivadinov, M.D., Ph.D.
A list of published papers along with contact information can be found elsewhere on BNAC.net.
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