Deep Gray Matter Iron and Disease Progression in Multiple Sclerosis

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PROJECT SUMMARY Tissue loss in the thalamus is one of the earliest imaging hallmarks of multiple sclerosis. However, the current inability to study tissue alterations non-invasively on the cellular and molecular level in the different sub-regions of the deep gray matter, which fulfill distinct functional roles, represents a critical barrier for understanding and targeting biological mechanisms that may precede or interact with neurodegeneration. Magnetic resonance imaging of magnetic tissue susceptibility represents a unique window through which tissue iron can be assessed clinically. Iron is an essential co-factor in various biochemical pathways. Its deprivation from glial cells in the normal-appearing white matter is a pathological hallmark of multiple sclerosis that has been implicated in neuronal injury. It was recently observed that the thalamus of patients with multiple sclerosis shows a progressive decline in magnetic susceptibility. Other research suggests that a similar phenomenon may exist in other deep gray matter regions. A critical need exists to confirm and validate this observation be- cause deep gray matter injury is strongly linked to the progression of disability. The overall objective of the proposed research is to determine whether disease progression is linked to iron-related oligodendroglia dysfunction in the deep gray matter. The central hypothesis is that declining oligodendroglial iron availability, as manifested on magnetic resonance imaging, is an independent biological correlate of disease progression that occurs throughout the brain. The rationale for the proposed research is that a link between iron loss over time and disease progression will cause a paradigmatic shift in our understanding of the role of iron for neurodegen- eration away from the toxicity of excess iron toward an insufficient availability of iron for critical biochemical pathways. The project will pursue the following specific aims to achieve the objective: 1) Determine the associ- ation between disease progression and magnetic resonance imaging markers of brain iron homeostasis. 2) Identify the cellular and molecular substrate of magnetic resonance imaging markers of brain iron. Upon com- pletion of these aims, the expected outcome is to have determined that oligodendroglia iron is reduced in the chronic disease phase and that the progression to this state is linked to a worsening in disability. In particular, the research is expected to have determined a generalizable model of the evolution of imaging markers over time in patients relative to controls; cellular and molecular underpinnings of the imaging markers; and how im- aging markers of iron are linked to neurodegeneration and injury in the white matter. These contributions are expected to be significant because the evidence of a link between clinical disability and loss of oligodendroglial iron in the gray matter as well as the availability of an imaging marker to assess this phenomenon will advance the field vertically and support the development of new therapeutic strategies. The proposed research is inno- vative because the new hypothesis of iron loss, the focus on deep gray matter sub-regions, and a unique mod- eling approach for changes in iron concentration represent substantive departures from the status quo.