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 单心心脏病（SVHD）青少年表现出认知缺陷（〜50％受试者），影响 学术成就，自我保健能力，生活质量以及死亡率和发病率。大脑变化出现在 介导认知功能的区域（海马，扣带，岛状，尾状，尾状，前额叶，前额叶）。但是， SVHD中脑组织变化的基本过程尚不清楚，但可能包括较低O2的低氧血症 低心输出量的饱和度和脑血流减少（CBF）。慢性心输出量和 较低的O2饱和度在SVHD中很常见，导致缺氧，影响氧化应激和 线粒体功能障碍。线粒体功能障碍会改变代谢产物，包括N-乙酰基天冬氨酸（NAA； 神经元完整性），胆碱（CHO；膜代谢），创造（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，起着重要作用 针对氧化物应激，调节神经元/细胞保护免受过量活性氧。然而， SVHD中的区域脑代谢产物和抗氧化剂状态尚不清楚，可以使用3D Echo进行检查 平面光谱成像（3D EPSI）和Meshcher-Garwood Point分辨光谱法（Mega-- 按）。此外，CBF高度依赖心输出量，而心脏输出较低会导致减少 CBF，在完成手术疼痛后尚未报告。 CBF和下O2受损 饱和性可以进一步导致氧化应激，从而导致认知控制区域的组织变化，从而影响 关联的功能。可以通过动脉自旋标记成像，O2满意度来评估区域脑CBF 脉搏血氧饱和度和血清炎症生物标志物的氧化应激。那是使用25 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）和 SVHD和对照中的抗氧化剂（GSH；使用Mega-Press）； 2）使用ASL确定脑CBF差异 方法，基线O2饱和度，使用脉搏血氧饱和度，SVHD和对照之间以及关系 在区域CBF，O2饱和度和认知之间（使用记忆和学习的广泛评估 2）在SVHD患者中； 3）检查SVHD和对照中的炎症血清生物标志物，并将其关联 SVHD受试者中具有脑代谢物，CBF和O2饱和值的标记。总而言之，线粒体 以及有助于大脑代谢物和抗氧化剂变化的氧化应激机制减少了CBF 认知调节区域和血清炎症生物标志物以及SVHD中的这些措施之间的联系 将检查患者。这项R21探索性研究的结果将对 识别救援/恢复脑组织的治疗方法，这可能包括增加NAA的策略， 抗氧化剂和CR水平以及改善CBF，可以在大型临床试验中实施以改进 认知，学校表现以及降低的发病率和死亡率，并提高SVHD患者的生活质量。