Spontaneous intracerebral hemorrhage (ICH) is a common and often form of stroke. Up to 50% of patients die and half of survivors are left with significant disability. Though ICH occurs in about 10-15% of all strokes in the United States, the impact on long-term medical care costs and productivity loss is substantial. ICH costs $6 billion per year in the United States. In China, ICH accounts for up to a third of all strokes, a proportion that is much higher than in Western populations.
If a patient survives the initial bleed, the resulting hematoma within the brain parenchyma triggers a series of events leading to secondary insults and severe neurological deficits. Although the hematoma in humans gradually resolves, the neurological deficits in ICH patients are usually permanent and disabling. Clinical data suggests that iron overload plays a role in brain injury and atrophy following ICH. High levels of serum ferritin, an iron-binding protein, have been associated with poor outcome and severe brain edema in ICH patients; however, deferoxamine, an iron chelator has been found to reduce brain edema, neuronal death, brain atrophy, and neurological deficits in rats and pigs.
To address these challenges, the JI awarded funding to a new project “Quantitative measurements of brain iron overload after intracerebral hemorrhage.” According to Dr. Guohua Xi, Richard C Schneider Research Professor of Neurosurgery, UMMS, “brain iron overload is an attractive therapeutic target as it occurs over weeks and it may be amenable to delayed treatment; yet, the natural history of brain iron overload in ICH has not been well studied clinically or in large animal models.” “T2 magnetic resonance imaging (MRI),” he explains, “has been used to examine iron in the brain. However, whether it can be used to quantify brain iron levels in ICH and to examine the effects of iron chelation therapy has not been studied.”
This project aims to validate the utility of T2 imaging mapping in quantifying brain iron after ICH using a porcine model and to use this imaging technique to examine the natural history of brain iron accumulation after ICH and the effects of deferoxamine treatment on that accumulation in pigs and patients. As a biomarker, T2 mapping may provide a method of examining and optimizing iron chelation therapy and establishing a novel endpoint for ICH clinical trials. Dr. Xi adds that the long-term goal of the study is to establish a novel endpoint for ICH clinical trials. T2 mapping may provide a method of examining and optimizing iron chelation therapy as a biomarker.
“I have a strong interest in the project since it represents an overlap in my two main research interests, stroke and brain edema” Dr. Xi recalls “I was trained as a blood-CSF barrier neuropathologist during my post-doctoral fellowships and now have over 25-year experience working on blood-brain barriers with over 60 peer-reviewed papers on the subject. On coming to the University of Michigan, I expanded my focus to hemorrhagic stroke and have worked on animal and in vitro models of hemorrhagic stroke for the past 20 years and have over 70 peer-reviewed publications on the subject. There has been a particular focus on delineating brain injury mechanisms in cerebral hemorrhage. I have been continuously funded by NIH to work on brain edema and brain hemorrhage for the past 15 years.”
The co-investigators of this project have a long history of working together. Professor Yining Huang, Chairman and Professor from the Department of Neurology, First Hospital, PUHSC, remarks, “The current work is a part of a long-term collaboration between Dr. Xi and myself looking at brain injury after cerebral hemorrhage (intracerebral, subarachnoid, intraventricular).” Dr. Xi also points out that the rationale to collaborate with the PUSHC team is the strong basic ICH research at UM and a large number of ICH patients at PUHSC.
The experiments at UMMS aim to investigate brain iron quantitative T2 measurements in a pig ICH model, to determine the relationship between T2 values and brain iron concentrations, and to examine effects of deferoxamine on ICH-induced brain iron overload in pigs. Meanwhile, the studies at PUHSC are designed to learn the nature history of brain iron accumulation after ICH, and the effect of deferoxamine on brain iron overload in ICH patients.
Preliminary data at UM show that intracerebral hemorrhage results in a significant increase of brain iron. The dynamic changes of iron accumulation on analyzed MRI scans indicated a tendency for iron accumulation mainly inside the hematoma in the acute stage. It decreased slightly on the second week and gradually increased in the surrounding area of hematoma after that.
In April 2015, a proposal based on the pig MRI data was awarded an NIH Research Project Grant (R01) of $1.09 million, representing the desired goal for all projects that are funded by the JI. Both sides are satisfied with the collaboration and believe their work will ultimately contribute to improved patient care.