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

描述（由申请人提供）：美国每年出生的 400 万婴儿中，大约有 60,000 名婴儿体重低于 1,500 克（极低出生体重 - VLBW）。超过 12% 的婴儿遭受脑损伤并随后发育迟缓。尽管已经评估了各种神经保护策略，但没有一个成功。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 在动物模型中已被证明对发育中的大脑具有保护作用。我们的初步数据表明，其用于极低出生体重婴儿的疗效，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，这些早产儿在出生后 10 周内随机接受 Epo、Darbepoetin alfa（一种长效 ESA）或安慰剂/对照。第一批入组婴儿将于 2010 年 1 月达到 42-48 个月大。虽然该研究评估了 ESA 的安全性和一般短期发育影响，但现在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以及利用最先进的多模式神经影像学改善神经系统的潜在机制。 该提案旨在评估生命前 10 周内对 VLBW 婴儿施用 ESA 的纵向、长期发育影响和潜在神经机制。我们的具体假设是：1）新生儿期给予早产儿的 ESA 可改善长期神经发育结果，2）ESA 影响 MR 成像中反映的区域大脑结构、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，将通过在两个时间点进行全面的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（磁共振波谱）和局部脑血流（动脉自旋标记）。这项研究具有高度的临床相关性，因为长期发育和影像学随访研究是设计的一部分，显着提高了我们确定随机接受 ESA（一种用于早产儿的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。该提案解决了我们的长期目标，即通过更好地了解大脑行为关系来开发针对早产相关疾病的有效治疗策略。

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.