Hemorrhagic stroke constitutes 20 -30% of stroke cases in North America. It is one of the leading causes of death and neurological disability in the world. Hemorrhagic stroke is divided into Intra - cerebral hemorrhage (ICH), subarachnoid/intraventricular hemorrhage and subdural hemorrhage. There has been considerable progress over the past 20 years in animal and clinical studies to identify mechanisms of brain injury secondary to intracerebral hemorrhage. Studies are starting to identify that neurotoxicity contributed by Non-Heme iron is critical in determining the extent of neurological tissue damage. Increased amount of non heme iron surrounding the hematoma in an ICH has been shown to correlate with the size of the hematoma and also with the extent of neuronal damage. In animal models of ICH the effect of iron chelates has been demonstrated as reduction in the hematoma size and reduced extent of damage to neuronal tissue. This idea has led to phase I trial of such a chelate (Desferroxamine) in patients with ICH which has shown the safety and efficacy of an escalating dose. A phase II trial in ICH patients is underway to define the benefit in the human population. In general there is renewed vigor in identifying ways of quantifying tissue iron in other solid organs in the body. This is due to emergence of several iron chelate agents with a pharmacological profile favorable to the human physiology. Various MR based protocols have been examined to quantify iron in tissue with non-invasive imaging in other solid organs of the body. MR scanners with higher magnet strength and better resolution have demonstrated some promise in this regard. This technology can be hypothetically applied to the brain to ascertain the amount of iron in the brain tissue surrounding the hematoma in ICH patients. There is a clinical void and unmet need in the ICH patients of having a quantitative mechanism of risk stratification based on measured iron levels in the surrounding tissue following an ICH. A reliable set of MR sequences have not yet been established to help with iron quantification. This clinical gap in ICH management can be fulfilled by the proposed study to validate a reliable MRI protocol to enable consistent iron quantification in the brain tissue. We propose to quantify the iron concentration in the perihematomal brain tissue and be able to track the temporal variation in tissue levels over a period of 30 days following ICH. The background to our proposal is based on iron concentration phantom experiments and MRI R2* signal calculation correlating with the specified iron concentrations in the phantom. We have applied the MRI calculation algorithm from the phantom in a rat ICH model showing excellent correlation with tissue iron levels on histology following sacrifice of the animal. The proposed study is innovative because it utilizes existing susceptibility weighted sequence on MRI to actually measure tissue iron levels rather than merely detect the presence of iron. Once funded this study has the potential of establishing a tangible way of assessing severity of ICH based on iron toxicity and also may be a surrogate marker of functional outcome in the future.
Following a brain parenchymal hemorrhage there is lysis of red blood cells that cause deposition of iron in the brain tissue surrounding the hematoma. Brain iron accumulation can lead to brain cell death and consequent neurological deficits. There is no non-invasive method to estimate tissue iron in the brain at the immediate periphery of the hematoma. We propose to develop MRI based tissue iron quantification method to better assess the degree of brain damage following intracranial hemorrhage.
| Cao, Shenglong; Hua, Ya; Keep, Richard F et al. (2018) Minocycline Effects on Intracerebral Hemorrhage-Induced Iron Overload in Aged Rats: Brain Iron Quantification With Magnetic Resonance Imaging. Stroke 49:995-1002 |
