Might progressive MS result from excess brain iron that is released due to inflammation?

Ferdinand Schweser, Ph.D.

The State University of New York at Buffalo

Funded in September, 2017: $200000 for 3 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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Might progressive MS result from excess brain iron that is released due to inflammation?

Using MRI imaging, the researchers will gather initial evidence of whether chronic inflammation induces cells deep in the brain to release too much iron that leads to the progressive form of multiple sclerosis (MS) and perhaps other degenerative diseases as well.  

Several features of iron suggest that if too much of it is released in the brain, it can affect the function and vitality of brain cells and even lead to neurodegeneration. While iron is essential for many metabolic processes involved in brain functions, it also can fuel creation of highly reactive molecules, called radicals, that promote neurodegeneration.

The investigators hypothesize that in progressive MS, chronic inflammation fuels a vicious metabolic cycle that works this way: Substances released during inflammatory activity slowly release iron from cells called “oligodendrocytes.” These cells, which ordinarily require iron to maintain the neurons’ vitality, become progressively weaker and less able to protect and repair neurons. If neurons die due to reduced oligodendroglial function, brain circuitry is damaged. A region in which this damage may have a particularly wide-spread clinical effect is the highly connected gray matter that resides deep in the brain such as thalamus. Confirmation of their hypothesis would explain why anti-inflammatory therapies are largely ineffective in the progressive phase of MS. Their hypothesis also may explain why the frequency of inflammatory episodes in the early stages of MS correlates with neurodegeneration that occurs later in the disease process. 

They will test this hypothesis in progressive MS patients and in amodel of MS, using a comprehensive repertoire of advanced non-invasive MRI mapping techniques that they developed. They will measure iron in deep gray matter neurons with great accuracy using a technique they developed, called Quantitative Susceptibility Mapping (QSM), in combination with advanced spectroscopic techniques that allows them to measure neurotransmitter concentrations. Then they will see whether the iron levels in patients are correlated with iron levels seen in MS animal model brain tissues. If so, they will have validated this new technique for use in further exploring the mechanisms of iron depletion in neuroinflammation and neurodegeneration.  

Significance : This study may provide essential information for linking inflammation to neurodegeneration in progressive MS. If so, it would provide a foundation for testing new preventive or treatment approaches for this disease, and potentially for other neurodegenerative diseases like Alzheimer’s and Parkinson’s Disease.     

ABSTRACT

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Might progressive MS result from excess brain iron that is released due to inflammation?

A striking gap exists between our knowledge on brain iron and the growing body of evidence that many brain diseases, including multiple sclerosis (MS), Parkinson’s disease, and Alzheimer’s disease, are linked to a disturbed brain iron homeostasis. While we now understand that neuroinflammation is a major component of all these dis-eases, the involvement of iron remains contentious. A widely adopted hypothesis is that iron promotes neuro-degeneration via Fenton chemistry and, hence, has a primary role in disease progression. However, we recently found reduced iron in MS and Neuromyelitis Optica (NMO), which fundamentally challenges this current view of iron-overload as a major player in neurodegeneration. Our central hypothesis is that chronic activation of immune cells in the DGM induces bystander damage by fueling a metabolic cascade that depletes iron from oligodendro-cytes and causes progressive neuronal damage via oxidative stress and excitotoxicity. We will provide relevant data for a validation of our mechanistic hypothesis by studying MS as a model inflammatory disease. There is an urgent need to understand the precise mechanisms leading to neurodegeneration in secondary progressive MS (SPMS) because anti-inflammatory therapies are largely ineffective in this phase of the disease. In particular, the validation of our hypothesis will provide an explanation for the correlation between frequency of inflammatory episodes in the early stages of MS with late neurodegeneration and the progressive course. Our overall objective is the elucidation of the metabolic substrate of pathological processes that lead to sig-nal changes observed with in vivo iron MRI. Toward this end, we will validate the associations between iron and neurotransmitter homeostasis and cellular changes in the Theiler's Murine Encephalomyelitis Virus model of MS (Aim 1) and confirm the association in patients with SPMS (Aim 2). Due to their strong structural connectivity, DGM nuclei are especially prone to secondary neuro-inflammation along fiber tracts, naturally exposing them to increased inflammatory activity compared to other brain regions (“projected inflammation”). Our experimental strategy in this proposal focuses on the thalamus because, maintaining the richest connectivity profile of all brain regions, the thalamus may be particularly predisposed to damage from additional (projected) secondary inflamma-tion, such as cortical injury.

INVESTIGATOR BIOGRAPHIES

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Ferdinand Schweser, Ph.D.

Ferdinand Schweser, Ph.D., is Assistant Professor of Neurology and Biomedical Engineering and the Technical Director of MRI at the Center for Biomedical Imaging, Clinical and Translational Science Institute at the University at Buffalo, The State University of New York. He received his Ph.D. in Physics from the Friedrich Schiller University Jena, Germany where he worked with Dr. Reichenbach, a leader in the field of advanced susceptibility and phase MRI. Dr. Schweser's research interests lie in the area of quantitative biomedical magnetic resonance imaging (MRI). The general theme of his research seeks to explore the potential of MRI for clinical and pre-clinical imaging and to provide new and improved imaging technology with a direct clinical translational impact. Dr. Schweser has co-developed and pioneered quantitative susceptibility mapping (QSM), a technology that uses MRI in an entirely new way to quantify iron an myelin in the human brain.

The technique has since been applied in numerous clinical and pre-clinical studies involving multiple sclerosis, Parkinson's disease, neuromyelitis optica, and traumatic brain injury. His current research focuses on an improved understanding of the peculiar dynamics of the brain iron homeostasis in normal aging and its relationship to neuroinflammation. The goal of this endeavor is twofold: 1) to contribute deeper insight into the etiology, pathogenesis and potential treatment of neurodegenerative diseases that involve a disturbed iron homeostasis, and 2) to give clinicians the ability to diagnose diseases earlier and monitor them more accurately.

 

KEYWORDS


Anatomy: Axons
Basal ganglia
Central nervous system
Gray matter
Myelin

Thalamus
White matter
Conditions: Multiple Sclerosis
Function: Animal research
Technology:
MRI
Physics