The Impact of Cerebral Metabolic Stress on the Development of the Structural and Functional Connectome in Pediatric Sickle Cell Anemia

脑代谢应激对小儿镰状细胞贫血症结构和功能连接体发育的影响

• 批准号: 10594416
• 负责人: Melanie Erin Fields
• 金额: $ 56.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594416
• 关键词: Acute; Age; Algorithms; Anatomy; Attenuated; Biological Markers; Brain; Brain Injuries; Brain region; Cerebrum; Child; Childhood; Chronic; Clinical; Cognitive; Data; Development; Erythrocyte Transfusion; Evaluation; Executive Dysfunction; Exposure to; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Impaired cognition; Infarction; Injury; Intervention; Ischemia; Link; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolic stress; Metabolism; Nervous System Trauma; Outcome; Oxygen; Participant; Patient Care; Patients; Primary Prevention; Rest; Screening procedure; Sickle Cell Anemia; Stroke; Structure; Techniques; Testing; Time; Transcranial Doppler Ultrasonography; Transfusion; Treatment Efficacy; Vulnerable Populations; biomarker development; biomarker validation; brain magnetic resonance imaging; cognitive function; cognitive testing; cohort; comparison control; connectome; disability; efficacy evaluation; executive function; experience; improved; improved outcome; innovation; insight; neuroimaging; neuroimaging marker; novel; patient population; predictive marker; prevent; prospective; recruit; risk prediction model; risk stratification; stroke risk; treatment effect; white matter

PROJECT SUMMARY Children with sickle cell anemia (SCA) suffer from cognitive decline, even when unaffected by stroke. The pathophysiology of cognitive dysfunction in SCA is poorly understood. Understanding the mechanism and trajectory of injury and degree of reversibility is necessary to prevent lifelong disability in this vulnerable population. Furthermore, current screening tools are inadequate as transcranial Doppler ultrasound and structural brain MRI only screen for risk of stroke and evaluate for presence of irreversible infarction. The long- term goal of this proposal is to determine the mechanism of brain injury with MR measures of oxygen metabolism, structural connectivity, and functional connectivity, and develop neuroimaging biomarkers for cognitive dysfunction in SCA. Children with SCA experience cerebral metabolic stress, as measured by increased oxygen extraction fraction (OEF). OEF peaks within the deep white matter, co-localizing with the brain region at greatest risk for stroke in SCA. Increased metabolic stress is associated with disrupted connectivity within specific functional brain networks, and the nodes of networks with diminished functional connectivity in SCA are anatomically- contiguous, clustered and aligned with the region of elevated OEF in the white matter. However, OEF decreases and executive function abilities improve with a single red blood cell transfusion in children with SCA, suggesting some aspects of cognitive dysfunction, potentially driven by alterations in FC, are acutely reversible as metabolic stress is attenuated in SCA. The central hypothesis of this proposal is that isolated disruption of functional connectivity caused by increased metabolic stress will be acutely reversible; however, disruption of functional connectivity mediated by structural connectivity will be irreversible. Treatment of the former may improve cognitive function, while treatment of the latter may mitigate progressive cognitive decline. In order to test her hypothesis, Dr. Fields will obtain longitudinal measures, separated by three years, of cognitive testing and brain MRIs to measure OEF, structural connectivity and functional connectivity in control, non-transfused SCA, and transfused SCA participants. The transfused participants will undergo cognitive testing and brain MRI before and after red blood cell transfusion at study entrance. Using this data, she will test her central hypothesis by completing the following specific aims: 1) Determine if disruption of the structural and functional connectome is reversible with transfusion of RBCs in SCA, 2) Determine the impact of increased OEF on the development of the structural and functional connectome, and 3) Determine if MR metrics of metabolic stress, SC and FC predict aberrant cognitive trajectories. Completion of these aims will provide insight into the pathophysiology of cognitive dysfunction in SCA, and allow the definition and development of biomarkers for reversible neurologic injury, which can potentially guide treatment effect, and improve outcomes in this vulnerable population.

PROJECT SUMMARY Children with sickle cell anemia (SCA) suffer from cognitive decline, even when unaffected by stroke. The pathophysiology of cognitive dysfunction in SCA is poorly understood. Understanding the mechanism and trajectory of injury and degree of reversibility is necessary to prevent lifelong disability in this vulnerable population. Furthermore, current screening tools are inadequate as transcranial Doppler ultrasound and structural brain MRI only screen for risk of stroke and evaluate for presence of irreversible infarction. The long- term goal of this proposal is to determine the mechanism of brain injury with MR measures of oxygen metabolism, structural connectivity, and functional connectivity, and develop neuroimaging biomarkers for cognitive dysfunction in SCA. Children with SCA experience cerebral metabolic stress, as measured by increased oxygen extraction fraction (OEF). OEF peaks within the deep white matter, co-localizing with the brain region at greatest risk for stroke in SCA. Increased metabolic stress is associated with disrupted connectivity within specific functional brain networks, and the nodes of networks with diminished functional connectivity in SCA are anatomically- contiguous, clustered and aligned with the region of elevated OEF in the white matter. However, OEF decreases and executive function abilities improve with a single red blood cell transfusion in children with SCA, suggesting some aspects of cognitive dysfunction, potentially driven by alterations in FC, are acutely reversible as metabolic stress is attenuated in SCA. The central hypothesis of this proposal is that isolated disruption of functional connectivity caused by increased metabolic stress will be acutely reversible; however, disruption of functional connectivity mediated by structural connectivity will be irreversible. Treatment of the former may improve cognitive function, while treatment of the latter may mitigate progressive cognitive decline. In order to test her hypothesis, Dr. Fields will obtain longitudinal measures, separated by three years, of cognitive testing and brain MRIs to measure OEF, structural connectivity and functional connectivity in control, non-transfused SCA, and transfused SCA participants. The transfused participants will undergo cognitive testing and brain MRI before and after red blood cell transfusion at study entrance. Using this data, she will test her central hypothesis by completing the following specific aims: 1) Determine if disruption of the structural and functional connectome is reversible with transfusion of RBCs in SCA, 2) Determine the impact of increased OEF on the development of the structural and functional connectome, and 3) Determine if MR metrics of metabolic stress, SC and FC predict aberrant cognitive trajectories. Completion of these aims will provide insight into the pathophysiology of cognitive dysfunction in SCA, and allow the definition and development of biomarkers for reversible neurologic injury, which can potentially guide treatment effect, and improve outcomes in this vulnerable population.