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

描述（由申请人提供）：在美国每年出生的400万婴儿中，大约有6万婴儿体重不足1500克（极低出生体重vlbw）。这些婴儿中有超过12%的人遭受脑损伤，随后出现发育迟缓。虽然各种神经保护策略已被评估，但没有一个是成功的。迫切需要有效的干预措施来治疗这些最脆弱的婴儿。一种有希望的干预是使用重组红细胞生成素（Epo，也称为促红细胞生成剂，或ESA）。除了刺激红细胞生成外，在动物模型中，Epo已被证明对发育中的大脑有保护作用。我们有初步的数据表明，在有需要输血风险的VLBW婴儿中使用它是有效的，这些婴儿也有脑出血、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ESAs对早产儿的造血和短期发育影响，这些早产儿在出生前10周随机接受Epo、Darbepoetin α（一种长效ESA）或安慰剂/对照。第一批登记的婴儿将在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利用最先进的多模态神经成像技术改善神经系统的潜在机制。本研究旨在评估在出生后10周内对VLBW婴儿进行esa治疗的纵向、长期发育影响和潜在的神经机制。我们的具体假设是：1)在新生儿期给予早产儿欧空局改善长期神经发育结局；2)欧空局影响MR成像所反映的局部脑结构、神经化学和神经组织；3)血液中欧空局水平与MR成像和神经发育结局相关。为了验证这些假设，神经发育结果将通过在两个时间点进行全面的神经发育评估来评估：42-48个月和xx-xx个月（WPSSI III，早期儿童评估，执行分类电池）。脑成像将与发育评估同时进行，包括体积测量（高分辨率体积分析）、神经化学测量（磁共振波谱）和区域脑血流测量（动脉自旋标记）。由于长期发育和影像学随访研究是设计的一部分，因此该研究具有高度的临床相关性，显著提高了我们确定随机接受esa治疗的婴儿是否存在发育、功能和解剖差异的能力，esa是一种用于早产儿的相对较新的介入策略。这一建议解决了我们的长期目标，即通过提高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。

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.