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

使用去铁酮改善蛛网膜下腔出血的认知结果：U-DISCO

• 批准号: 10046985
• 负责人: David M. Hasan
• 金额: $ 72.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10046985
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amygdaloid structure; Aneurysmal Subarachnoid Hemorrhages; Animal Model; Animals; Apolipoprotein E; Atrophic; Attenuated; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Cells; Cerebral hemisphere hemorrhage; Chelating Agents; Clinical Research; Cognitive; Cognitive deficits; Cohort Studies; Confidence Intervals; Control Groups; Cytolysis; Data; Databases; Dementia; Development; Diffuse; Disease Progression; Double-Blind Method; Drainage procedure; Enrollment; Erythrocytes; Exposure to; Family; Ferritin; General Population; Grant; Hippocampus (Brain); Hospitals; Human; Impaired cognition; In Vitro; Intervention; Intraventricular; Ischemic Stroke; Lead; Lipids; Magnetic Resonance Imaging; Measures; Medical; Memory impairment; Neurologic Deficit; Neurons; Outcome; Pathway interactions; Phase; Placebos; Process; Protocols documentation; Randomized; Reporter; Risk; Standardization; Stroke; Structure; Subarachnoid Hemorrhage; Subarachnoid Space; Survivors; Testing; Therapeutic Agents; Therapeutic Effect; Translating; Work; age group; animal data; base; cognitive change; cognitive function; cognitive performance; cognitive testing; cohort; genetic risk factor; hazard; high risk; human model; imaging study; improved; intraventricular hemorrhage; mild cognitive impairment; mortality; mouse model; neuroimaging; neuron loss; population based; post stroke; preclinical study; recruit; risk variant; sex; standard of care; stroke survivor; years of life lost

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.

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