Neurocognitive and neuroimaging markers of emerging cerebral adrenoleukodystrophy

项目摘要/摘要 肾上腺脑白质营养不良(ALD)是一种进行性X-连锁神经系统疾病，在 表情。在儿童时期，大约每3个男孩中就有1个发展迅速，发展为伴有大脑的脑性ALD 炎症和髓鞘破坏。尽管现有的治疗方法在以下情况下会阻止脑部ALD的进展 在早期阶段被检测到，目前没有任何评估可以确定哪些男孩会患上大脑ALD，或者什么时候会 一切都会开始的。在出生时识别ALD的新生儿筛查计划提供了一个机会，可以更早地提供 避免不可逆转的神经认知衰退的治疗，而新的治疗方法可能会提供更安全的替代方案 到标准的干细胞疗法。这项K23职业发展奖旨在为PI提供必要的 培训成为一名独立调查员，精通跨模式方法来衡量细微之处 ALD儿童的大脑变化，并将这些方法应用于临床研究方案。有良师益友 在明尼苏达大学的一个专家团队中，申请者提出了以下培训目标： (1)获取获取和分析神经影像数据的知识和经验；(2)学习统计学 和验证新的神经认知测试的计算方法；以及(3)获得以下专业知识 设计和执行临床试验。总体研究目标旨在确定早期神经认知 和神经影像标志物的脑脱髓鞘和增强能力的临床试验较新 为接受早期治疗的男孩确定强有力的终点的治疗。中心假设是 白质纤维完整性的恶化以及与之相关的累及大脑皮质的大脑间功能丧失 痂标志着大脑ALD的开始，在MRI上出现病变之前就开始了。为了测试这一点 假设，PI将测试几种旨在测量与脱髓鞘相关的变化的方法。这个 特定的AIMS将使用纵向神经认知测试(AIM 1)和纵向弥散磁共振研究(AIM 2) 目的：确定早期疾病男童脑组织碱性磷酸酶的功能和微结构标志物，并检测 高危男童发病前关键阶段中这些标志物的存在。神经认知的发现 也将与疾病进展的MRI指标进行比较。这些目标的成功实现将 确定疾病开始和早期进展的可靠指标。这项拟议的研究具有重要意义 因为检测和量化患有ALD的男孩大脑细微的进行性变化将使我们更早地 并采取更有效的干预措施，降低神经认知功能的发病率。培训目标将支持 申请人的职业目标是领导一项长期的研究计划，以确定大脑的敏感标志物 神经发育和神经退行性疾病的功能障碍，目的是通知时间和 干预措施的有效性，以实现更好的患者结局。

Project Summary/Abstract Adrenoleukodystrophy (ALD) is a progressive X-linked neurological disorder with unpredictable variation in expression. During childhood, about 1 in 3 boys develop rapidly progressing cerebral ALD with brain inflammation and myelin destruction. Although existing treatments stop progression of cerebral ALD when detected at an early stage, no current assessments can identify which boys will develop cerebral ALD or when it will begin. Newborn screening programs that identify ALD at birth offer an opportunity to provide earlier treatment that avoids irreversible neurocognitive decline while new treatments may present safer alternatives to standard stem cell therapy. This K23 Career Development Award aims to provide the PI with the necessary training to become an independent investigator proficient in cross-modal methodologies to measure subtle brain changes in children with ALD and apply those methods in clinical research protocols. With mentorship from a team of experts at the University of Minnesota, the applicant proposes the following training objectives: (1) to obtain knowledge and experience in acquisition and analysis of neuroimaging data; (2) to learn statistical and computational methods for validation of novel neurocognitive tests; and (3) to acquire the expertise to design and execute clinical trials. The overall research objectives are designed to identify early neurocognitive and neuroimaging markers of cerebral demyelination and enhance the capacity of clinical trials of newer therapies to define robust endpoints for boys who receive early treatment. The central hypothesis is that deterioration in white matter fiber integrity and associated loss of interhemispheric function involving the corpus callosum mark the onset of cerebral ALD, and begin prior to the appearance of a lesion on MRI. To test this hypothesis, the PI will test several methods designed to measure changes associated with demyelination. The specific aims will use longitudinal neurocognitive testing (Aim 1) and longitudinal diffusion MRI studies (Aim 2) to identify functional and microstructural markers of cerebral ALD in boys with early stage disease, and test for presence of these markers during the critical pre-emergent stage in at-risk boys. The neurocognitive findings will also be compared to MRI metrics of disease progression. The successful completion of these Aims will identify reliable indicators of disease onset and early progression. The proposed research is significant because detection and quantification of subtle progressive brain changes in boys with ALD will allow earlier and more effective intervention to reduce the neurocognitive morbidity. The training objectives will support the applicant's career goals to lead a long-term program of research to identify sensitive markers of brain dysfunction in neurodevelopmental and neurodegenerative diseases, with the goal of informing timing and efficacy of interventions to achieve better patient outcomes.