The Use of Deferiprone to Improve Subarachnoid Hemorrhage Cognitive Outcome: U-DISCO

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Project Summary: Aneurysmal subarachnoid hemorrhage (aSAH) has a high mortality rate (~60%), with a large proportion of the survivors becoming functionally dependent. aSAH survivors have long term cognitive deficits and memory impairment in their productive years with major responsibilities with respect to work and family. In a 30-year nationwide population-based cohort study using data from Danish medical databases, the authors computed the absolute risks and hazard ratios (HR) of dementia up to 30 years after stroke. Compared with the general population, the HR (95% confidence interval) for dementia among ischemic stroke survivors was 1.72 (1.66–1.77), 2.70 (2.53–2.89) after intracerebral hemorrhage, and 2.74 (2.45–3.06) after aSAH. Why is that?? In aSAH subjects, accumulation of hemoglobulin (Hb) and non-heme iron (Fe) which are the natural byproduct lysis of red blood cells leads to significant neuronal cells death. Several preclinical studies in animals showed that both products lead to neuronal death and atrophy of any brain structures exposed to it and specifically the hippocampus and amygdala. These data were replicated in human, where authors found, the level of ferritin (Ft) in CSF, a reporter of the amount of Fe in brain, was found to strongly correlate with progression to Alzheimer's disease (AD). What is the mechanistic pathway of this process?? Our group showed that Hb is toxic to neuronal cells in vitro and adding deferiprone (De) attenuated and reversed this effect significantly. We then confirmed these results in a mouse model of intraventricular hemorrhage. Additionally, in a proof-of-concept study we showed that De significantly decreased Ft in CSF (p<0.0001) suggesting a potential therapeutic effect. Furthermore, others also showed in preclinical studies using different animal models, Fe chelating agents decrease Fe content both in the subarachnoid space and intraventricular improving the functional and cognitive outcome in these animals. Therefore, we propose this grant to test the hypothesis that deferiprone, a lipid soluble Fe chelating agent and therefore diffuse easily across the blood-brain barrier, will significantly decrease Ft (a reporter of total non-heme Fe content in CSF) in subjects with aSAH and hence improve cognitive function. To test this hypothesis, we propose a phase 1/2a single-center randomized double-blinded placebo vs. De trial that recruits and enrolls 66 subjects with aSAH who require placement of EVD as a standard of care. Subjects will be randomized equally into 2 groups: A) placebo & B) 15 mg/kg bid for 21 days. Ft will be collected daily from CSF. We will also test the cognitive changes using the Montreal Cognitive Assessment test along with a battery of well-standardized and widely used cognitive tests that measure various aspects of cognitive and behavioral functioning. We will also assess the volume of hippocampus and amygdala in this cohort and compare them to a matched, historic control cohort using specific MRI protocol. These tests will be correlated with the Ft content in CSF and the volume of hippocampus and amygdala on imaging studies obtained.