MR-Derived Cerebral Oxygen Metabolism underlying Ischemic Vulnerability in Sickle Cell Disease

镰状细胞病缺血性脆弱性背后的磁共振衍生脑氧代谢

• 批准号: 10204087
• 负责人: Hongyu An
• 金额: $ 67.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10204087
• 关键词: Adhesions; Adult; Affect; Age; Aging; Anemia; Binding; Biological Markers; Blood; Blood Vessels; Blood capillaries; Body Weight; Bone Marrow Transplantation; Brain; Cell Adhesion Molecules; Cerebral Hypoxia; Cerebral Infarction; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Trials; Core-Binding Factor; Cytokine Activation; Data; Diffusion; Disease; Employment; Endothelium; Energy Metabolism; Erythrocytes; Erythropoiesis; Failure; Grant; Growth; Hemolytic Anemia; Heterogeneity; Hypoxia; Impaired cognition; Individual; Infarction; Inflammation; Investigation; Ischemia; Ischemic Brain Injury; Kinetics; Leukocytes; Life Expectancy; Magnetic Resonance Imaging; Measures; Metabolic; Metabolic stress; Metabolism; Methods; Microvascular Dysfunction; Morphology; Neonatal Screening; Neurocognitive; Neurologic; Organ; Oxygen; P-Selectin; Patients; Pattern; Physiology; Plasma Proteins; Population; Predisposition; Race; Rest; Risk; Screening procedure; Selectins; Shapes; Sickle Cell; Sickle Cell Anemia; Specificity; Stroke; Surface; Testing; Time; Tissues; Tracer; Transfusion; Unemployment; Vascular blood supply; Work; base; brain cell; brain tissue; cerebral ischemic injury; clinical predictors; cognitive disability; cognitive performance; cognitive testing; cohort; cytokine; density; disability; disorder risk; experience; follow-up; hemodynamics; high risk; hydroxyurea; illness length; imaging biomarker; inhibitor/antagonist; interest; ischemic injury; neuroimaging; neuroinflammation; neuroprotection; new therapeutic target; novel; polymerization; predictive signature; premature; sickling; spectrograph; stroke risk; systemic inflammatory response; vaso-occlusive crisis; white matter; young adult

Abstract: Sickle cell anemia (SCA) affects one in 1000 individuals worldwide, causing multi-organ ischemia, long-term disability, and premature death, with a life expectancy of 42 years. Among its complications, cerebral infarction and cognitive disability are prevalent and increase with age, with > 50% of young adults having silent infarcts. Great headway has been made in pediatric SCA using neuroimaging screening tools to select high-risk children, yet adults remain understudied. As the brain demands disproportionately more oxygen than other organs at ~20% of total blood supply (but only 2% of body weight), low arterial oxygen content (CaO2) due to anemia, places the sickle cell brain at lifelong risk of hypoxia. Thus, to try to meet cerebral oxygen demand (CMRO2), the brain is continually under hemodynamic and metabolic “stress”, marked by elevated cerebral blood flow and oxygen extraction fraction (OEF), respectively. Findings from our previous grant cycle have helped shape a new understanding of ischemic brain injury mechanisms in SCA. Importantly, specificity of both global and regional OEF for stratifying stroke risk, at patient and tissue levels, suggests great promise for the clinical utility of this imaging biomarker. We are now completing follow-up MRIs to determine if OEF longitudinally predicts infarction in pediatric SCA. Two unexpected findings emerged from our results which warrant further investigation. First, we expected that compensatory increases in CBF and OEF in SCA would serve to maintain a normal cerebral oxygen metabolic demand; however, we found that resting CMRO2 is globally elevated in SCA. This increase in oxygen demand parallels an elevation in total body resting energy expenditure in SCA, which is postulated to be due to chronic inflammation. The finding is intriguing as an elevated cerebral oxygen demand may increase ischemic vulnerability. Indeed, sickling and high blood velocity injure the endothelium inducing a variety of leukocyte-endothelial interactions. Therefore, we hypothesize that neuroinflammation may promote ischemia by increasing cerebral oxygen demand. Second, while we find global OEF elevation in adults with SCA compared to controls, regional OEF elevation in the deep white matter is less prominent in adults compared to children, suggesting a decrease in regional OEF with disease duration. It is postulated that capillary flow heterogeneity (CFH) due to change in capillary microarchitecture leads to a reduction in local OEF. This is of great interest in SCA because capillary morphology is disrupted and transit times are short due to anemia. Thus, we hypothesize that progressive microvascular disease in SCA will disrupt capillary flow patterns, decreasing oxygen supply, as an additional ischemic mechanism. In this renewal, we shift focus to adults with SCA, as a growing and understudied population. First, we will determine if cerebral metabolic stress predicts ischemic brain injury and cognitive decline. Next, we will employ novel MR approaches to investigate two mechanisms (neuro- inflammation and CFH) which perturb cerebral oxygen metabolic physiology, to further our understanding of oxygen supply-demand mismatch in SCA, each which can be developed as a novel therapeutic target.

摘要：镰状细胞性贫血（SCA）在全世界每1000人中就有1人发病，可引起多器官缺血。