Brain Metabolites, Brain Antioxidant, and Cerebral Blood Flow Deficits in Single Ventricle Heart Disease

单心室心脏病中的脑代谢物、脑抗氧化剂和脑血流缺陷

• 批准号: 10644553
• 负责人: Rajesh Kumar
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644553
• 关键词: 3-Dimensional; Academic achievement; Adolescent; Affect; Angiotensins; Antioxidants; Area; Astrocytes; Behavior Therapy; Biological Markers; Brain; Brain Injuries; Brain Stem; Brain region; C-reactive protein; Carbon Dioxide; Cardiac Output; Cardiovascular system; Cerebrovascular Circulation; Child; Choline; Chronic; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Complex; Contrast Media; Creatine; Defense Mechanisms; Diffusion; Dipyridamole; Disease; Energy Metabolism; Equilibrium; Etiology; Exercise; Fetus; Glutathione; Health; Hippocampus; Hypoxemia; IL8 gene; Image; Imaging Techniques; Impairment; Inflammatory; Insula of Reil; Interleukin-1 beta; Interleukin-6; Learning; Link; Low Cardiac Output; Measures; Mediating; Membrane; Memory; Metabolism; Methods; Mitochondria; Morbidity - disease rate; N-acetylaspartate; Neurons; Operative Surgical Procedures; Osmosis; Outcome; Oxidative Stress; Oxidative Stress Induction; Patients; Performance; Physiology; Pilot Projects; Play; Positron-Emission Tomography; Prefrontal Cortex; Process; Production; Proliferating; Pulse Oximetry; Quality of life; Radiation; Reactive Oxygen Species; Reporting; Reproducibility; Role; Schools; Self Care; Serum; Short-Term Memory; Single ventricle congenital heart disease; Site; Spectrum Analysis; TNF gene; Tissues; arterial spin labeling; brain dysfunction; brain tissue; cognitive benefits; cognitive control; cognitive function; congenital heart disorder; effective intervention; gray matter; high risk; improved; insight; mechanical circulatory support; mitochondrial dysfunction; mortality; myoinositol; palliation; patient population; spectroscopic imaging; tissue injury

PROJECT SUMMARY/ ABSTRACT Single ventricle heart disease (SVHD) adolescents show cognitive deficits (~50% subjects), affecting academic achievement, self-care ability, quality of life, and mortality and morbidity. Brain changes appear in areas (hippocampus, cingulate, insula, caudate, prefrontal) that mediate cognitive functions. However, the underlying processes for brain tissue changes in SVHD are unclear, but may include hypoxemia from lower O2 saturation and reduced cerebral blood flow (CBF) from low cardiac output. Chronically low cardiac output and lower O2 saturation are common in SVHD contributing to hypoxemia that induces oxidative stress and mitochondrial dysfunction. Mitochondrial dysfunction alters metabolites, including the N-acetyl-aspartate (NAA; neuronal integrity), choline (Cho; membrane metabolism), creatine (Cr; energy metabolism), and myo-inositol (MI; astrocyte proliferation). Also, antioxidants, including glutathione (GSH) levels that play a significant role against oxidative stress, regulate neuronal/cellular protection from excessive reactive oxygen species. However, regional brain metabolites and antioxidant status in SVHD is unknown that can be examined with the 3D Echo Planar Spectroscopic Imaging (3D EPSI) and the MEshcher–GArwood Point RESolved Spectroscopy (MEGA- PRESS). In addition, CBF is highly dependent on cardiac output, and lower cardiac output can result to reduced CBF, which has not been reported after completed staged surgical palliation. Impaired CBF and lower O2 saturation can further contribute to oxidative stress, leading to tissue changes in cognitive control areas, affecting associated functions. Regional brain CBF can be assessed by arterial spin labeling imaging, O2 saturation with pulse oximetry, and oxidative stress with serum inflammatory biomarkers. Thus, using 25 SVHD and 25 healthy controls, the specific aims are to: 1) assess whole-brain metabolites (NAA, Cho, Cr, and MI; using 3D EPSI) and antioxidant (GSH; using MEGA-PRESS) in SVHD and controls; 2) identify brain CBF differences, using ASL methods, baseline O2 saturation levels, using pulse oximetry, between SVHD and controls, and relationships between regional CBF, O2 saturation, and cognition (using the Wide Range Assessment of Memory and Learning 2) in SVHD patients; and 3) examine inflammatory serum biomarkers in SVHD and controls, and correlate those markers with brain metabolites, CBF, and O2 saturation values in SVHD subjects. In summary, mitochondrial and oxidative stress mechanisms contributing to changes in brain metabolites and antioxidant, reduced CBF in cognitive regulatory areas, and serum inflammatory biomarkers, as well as links among these measures in SVHD patients will be examined. The outcomes from this R21 exploratory study will have significant implications on identification of treatments for rescue/restore brain tissue that might include strategies to increase NAA, antioxidant, and Cr levels, as well as improve CBF, and could be implemented on a large clinical trial to improve cognition, school performance, and reduced morbidity and mortality, and increased life quality in SVHD patients.

项目摘要/摘要 单心室心脏病（SVHD）青少年表现出认知缺陷（约50%的受试者）， 学习成绩、自理能力、生活质量、死亡率和发病率。大脑的变化出现在 调节认知功能的区域（海马、扣带回、尾状核、前额叶）。但 SVHD脑组织变化的潜在过程尚不清楚，但可能包括低氧血症 低心输出量导致的脑血流量（CBF）减少。慢性低心排血量， 较低的O2饱和度在SVHD中很常见，导致低氧血症，引起氧化应激， 线粒体功能障碍线粒体功能障碍改变代谢物，包括N-乙酰天冬氨酸（NAA; 神经元完整性）、胆碱（Cho;膜代谢）、肌酸（Cr;能量代谢）和肌醇 (MI星形胶质细胞增殖）。此外，抗氧化剂，包括谷胱甘肽（GSH）水平发挥重要作用， 抗氧化应激，调节神经元/细胞保护免受过量的活性氧。然而，在这方面， SVHD患者的局部脑代谢物和抗氧化状态未知，可使用3D Echo进行检查 平面光谱成像（3D EPSI）和MEshcher-GArwood点分辨光谱（MEGA- Press）。此外，CBF高度依赖于心输出量，较低的心输出量可导致脑血流减少。 CBF，在完成分期手术姑息治疗后尚未报告。CBF受损和O2降低 饱和可以进一步促进氧化应激，导致认知控制区域的组织变化，影响 相关功能。局部脑CBF可以通过动脉自旋标记成像、氧饱和度和脑血流灌注来评估。 脉搏血氧仪和氧化应激与血清炎症生物标志物。因此，使用25个SVHD和25个健康 对照组，具体目的是：1）评估全脑代谢物（NAA、Cho、Cr和MI;使用3D EPSI）， 抗氧化剂（GSH;使用MEGA-PRESS）在SVHD和对照组; 2）确定脑CBF差异，使用ASL 方法，基线O2饱和度水平，使用脉搏血氧仪，SVHD和对照之间，以及关系 区域CBF，O2饱和度和认知之间的关系（使用记忆和学习的广泛评估 2)在SVHD患者中;和3）检查SVHD和对照中的炎性血清生物标志物，并将这些生物标志物 SVHD受试者的脑代谢物、CBF和O2饱和度值。总之，线粒体 氧化应激机制导致脑代谢物和抗氧化剂的变化， 认知调节区和血清炎症生物标志物，以及这些措施之间的联系，在SVHD 患者将接受检查。这项R21探索性研究的结果将对以下方面产生重大影响： 鉴定用于挽救/恢复脑组织的治疗，其可能包括增加NAA的策略， 抗氧化剂和Cr水平，以及改善CBF，并可以在大型临床试验中实施，以改善 认知，学校表现，降低发病率和死亡率，提高SVHD患者的生活质量。