Brain imaging and developmental follow-up of infants treated with erythropoietin

促红细胞生成素治疗婴儿的脑成像和发育随访

• 批准号: 8055990
• 负责人: ROBIN K OHLS
• 金额: $ 47.15万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-06 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055990
• 关键词: Address; Affect; Age; Animal Model; Anterior; Antioxidants; Behavioral; Biochemical; Blood; Brain; Brain Injuries; Brain hemorrhage; Brain imaging; Caring; Cerebrovascular Circulation; Cerebrum; Child; Cognition; Cognitive; Colorado; Creatine; Data; Development; Developmental Delay Disorders; Disease; Enrollment; Erythrocytes; Erythropoiesis; Erythropoietin; Evaluation; Follow-Up Studies; Funding; Gestational Age; Glutamates; Glutamine; Goals; Gray unit of radiation dose; Growth; Head; Hematopoietic; Hospitalization; Hypoxia; Image; Incidence; Infant; Inflammation; Injury; Intervention; Ischemic-Hypoxic Encephalopathy; Language; Left; Life; Long-Term Effects; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Motor Skills; Multicenter Studies; Neonatal; Neonatal Intensive Care Units; Neurocognition; Neurocognitive; Neurologic; Neuronal Plasticity; Neurons; New Mexico; Nitric Oxide; Outcome; Placebo Control; Predisposition; Premature Birth; Premature Infant; Production; Provider; Randomized; Recombinant Erythropoietin; Research; Research Design; Resolution; Risk; Safety; Serum; Spin Labels; Structure; Testing; Time; Toxic effect; Transfusion; Ultrasonography; United States; Universities; Utah; Very Low Birth Weight Infant; axonal degeneration; base; brain behavior; cingulate gyrus; clinically relevant; darbepoetin alfa; design; effective intervention; effective therapy; executive function; follow-up; frontal lobe; high risk infant; improved; intraventricular hemorrhage; neurochemistry; neurogenesis; neuroimaging; neuron apoptosis; premature; prevent; protective effect; public health relevance; recombinant human erythropoietin; response; treatment strategy; visual motor; white matter

DESCRIPTION (provided by applicant): Of the 4 million infants born each year in the United States, approximately 60,000 weigh less than 1,500 grams (very low birth weight-VLBW). Over twelve percent of these infants sustain brain injury with subsequent developmental delay. Although various neuroprotective strategies have been evaluated, none have been successful. Effective interventions are desperately needed to treat these most vulnerable of infants. One promising intervention is the use of recombinant erythropoietin (Epo, also known as an erythropoiesis stimulating agent, or ESA). In addition to stimulating red cell production, Epo has been shown to be protective in the developing brain in animal models. We have preliminary data suggesting its efficacy when used in VLBW infants, who are at risk of requiring transfusions, and who are also at risk for brain hemorrhage, hypoxic- ischemic brain injury, and developmental delay. We are currently performing a multicentered study evaluating hematopoietic and short term developmental effects of ESAs in preterm infants randomized to receive Epo, Darbepoetin alfa (a longer acting ESA), or placebo/ control for the first 10 weeks of age. The first enrolled infants will reach 42-48 months in January, 2010. While that study evaluates the safety and general short-term developmental effects of ESAs, there is an unprecedented opportunity to study long term effects of ESA in significant detail, including evaluating the long term developmental effects and the underlying mechanism of neurologic improvement with state of the art multimodal neuroimaging. This proposal seeks to evaluate longitudinal, long-term developmental effects and underlying neurologic mechanisms of ESAs administered to VLBW infants in the first 10 weeks of life. Our specific hypotheses are: 1) ESAs administered to preterm infants during the neonatal period improve long-term neurodevelopmental outcome, 2) ESAs affect regional brain structure, neurochemistry and neurologic organization as reflected in MR imaging, and 3) the blood level of ESA correlates with MR imaging and neurodevelopmental outcome. To test these hypotheses, neurodevelopmental outcome will be assessed through a comprehensive neurodevelopmental assessment at two time points: 42-48 months, and xx-xx months (WPSSI III, Early Child Assessment, Executive Categorization Battery). Brain imaging will be performed concurrent with developmental assessments and includes measures of volume (high resolution volumetric analysis), neurochemistry (magnetic resonance spectroscopy) and regional cerebral blood flow (arterial spin labeling). This study is highly clinically relevant due to the long-term developmental and imaging follow up studies that are part of the design, significantly increasing our ability to determine if developmental, functional and anatomical differences exist in infants randomized to ESAs, a relatively new interventional strategy used in preterm infants. This proposal addresses our long-term goal of developing effective treatment strategies for disorders associated with prematurity through an improved understanding of brain-behavioral relationships. PUBLIC HEALTH RELEVANCE: Approximately 60,000 premature infants are born each year who weigh less than 1,500 grams, many of whom sustain brain damage because of their prematurity. This study is designed to evaluate the long-term developmental effects of one promising neuroprotective treatment, erythropoietin, when given in the neonatal period. Using detailed longitudinal neurodevelopmental assessments and state-of-the-art neuroimaging, we hope to determine whether this is an effective treatment to prevent brain damage associated with prematurity, and to lay the groundwork for further studies using principles of neuroplasticity to improve the developmental outcome of premature delivery.

描述（由申请人提供）：在美国每年出生的400万婴儿中，约有60，000名体重低于1，500克（极低出生体重-VLBW）。超过12%的婴儿遭受脑损伤，随后发育迟缓。虽然已经评估了各种神经保护策略，但没有一种是成功的。迫切需要有效的干预措施来治疗这些最脆弱的婴儿。 一种有希望的干预措施是使用重组促红细胞生成素（Epo，也称为红细胞生成刺激剂，或ESA）。除了刺激红细胞生成外，Epo还被证明在动物模型中对发育中的大脑具有保护作用。我们有初步数据表明其在极低出生体重婴儿中使用时的疗效，这些婴儿有需要输血的风险，也有脑出血、缺氧缺血性脑损伤和发育迟缓的风险。我们目前正在进行一项多中心研究，评估ESA对早产儿造血和短期发育的影响，这些早产儿在前10周龄随机接受Epo、Darbepopotera alfa（一种长效ESA）或安慰剂/对照。第一批入组的婴儿将于2010年1月达到42-48个月。虽然该研究评估了ESA的安全性和一般短期发育影响，但有一个前所未有的机会来详细研究ESA的长期影响，包括评估长期发育影响和最先进的多模式神经成像的神经改善的潜在机制。 本提案旨在评估在出生后前10周给予极低出生体重婴儿ESA的纵向、长期发育影响和潜在神经学机制。我们的具体假设是：1）新生儿期给予早产儿ESA可改善长期神经发育结果，2）ESA影响MR成像中反映的局部脑结构、神经化学和神经组织，3）ESA的血液水平与MR成像和神经发育结果相关。为了检验这些假设，将通过两个时间点的全面神经发育评估来评估神经发育结果：42-48个月和xx-xx个月（WPSSI III、早期儿童评估、执行分类组合）。脑成像将与发育评估同时进行，包括测量体积（高分辨率体积分析）、神经化学（磁共振波谱）和局部脑血流量（动脉自旋标记）。本研究具有高度临床相关性，因为长期发育和成像随访研究是设计的一部分，显著提高了我们确定随机分配至ESA（早产儿中使用的一种相对较新的干预策略）的婴儿是否存在发育、功能和解剖学差异的能力。该提案涉及我们的长期目标，即通过改善对大脑行为关系的理解，为与早产相关的疾病制定有效的治疗策略。 公共卫生相关性：每年大约有60，000名体重不足1，500克的早产儿出生，其中许多人因早产而遭受脑损伤。本研究旨在评估一种有前途的神经保护治疗，促红细胞生成素，在新生儿期给予的长期发育影响。使用详细的纵向神经发育评估和最先进的神经成像，我们希望确定这是否是一种有效的治疗方法，以防止与早产相关的脑损伤，并为进一步研究奠定基础，使用神经可塑性的原则，以改善早产的发育结果。