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，约有6万婴儿的体重低于1500克(极低出生体重-VLBW)。在这些婴儿中，超过12%的人患有脑损伤，并随后出现发育迟缓。尽管已经对各种神经保护策略进行了评估，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)。除了刺激红细胞的产生，EPO已经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，它在VLBW婴儿中使用时的有效性，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延迟的风险。我们目前正在进行一项多中心研究，评估ESA对早产儿的造血和短期发育影响，早产儿随机接受EPO、Darbepoetin Alfa(长效ESA)或安慰剂/对照组的前10周治疗。第一批登记的婴儿将在2010年1月达到42-48个月。虽然这项研究评估了ESA的安全性和一般的短期发育影响，但有一个前所未有的机会来研究ESA的长期影响，包括利用最先进的多模式神经成像评估ESA的长期发育影响和神经改善的潜在机制。本研究旨在评估极低出生体重(VLBW)婴儿出生后10周内给予ESA的纵向、长期发育效应和潜在的神经学机制。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影响磁共振成像所反映的局部脑结构、神经化学和神经组织，3)ESA的血水平与MR成像和神经发育结果相关。为了验证这些假设，神经发育结果将通过两个时间点的综合神经发育评估进行评估：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，包括容量(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)的测量。这项研究具有高度的临床相关性，因为长期的发育和影像随访研究是设计的一部分，显著提高了我们确定随机使用ESA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干预策略。这项建议解决了我们的长期目标，即通过改善对大脑-行为关系的理解，开发与早产相关的障碍的有效治疗策略。

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.