Neurocognitive and neuroimaging markers of emerging cerebral adrenoleukodystrophy

新发脑性肾上腺脑白质营养不良的神经认知和神经影像学标志物

• 批准号: 10678672
• 负责人: Elizabeth Irene Pierpont
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-08 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678672
• 关键词: 10 year old; Adrenal gland hypofunction; Adrenoleukodystrophy; Adrenomyeloneuropathy; Affect; Appearance; Attention; Behavior assessment; Behavioral; Birth; Brain; Brain Diseases; Cerebrum; Cessation of life; Child; Childhood; Clinical; Clinical Research Protocols; Clinical Trials; Clinical Trials Design; Computing Methodologies; Corpus Callosum; Data; Demyelinating Diseases; Demyelinations; Detection; Deterioration; Development; Development Plans; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Disease Progression; Early identification; Early treatment; Encephalitis; Fiber; Fingers; Funding; Future; Goals; Guidelines; Hematopoietic Stem Cell Transplantation; Individual; Informal Social Control; Investigation; Investigational Therapies; K-Series Research Career Programs; Knowledge; Lesion; Link; Magnetic Resonance Imaging; Measures; Mentorship; Methodology; Methods; Minnesota; Modality; Monitor; Morbidity - disease rate; Myelin; Neonatal Screening; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurodevelopmental Disorder; Onset of illness; Outcome; Pathogenicity; Patient-Focused Outcomes; Patients; Protocols documentation; Public Health; Recommendation; Research; Research Design; Research Personnel; Risk; Statistical Methods; Testing; Training; Treatment Efficacy; Universities; Validation; Variant; Work; attentional control; boys; brain dysfunction; brain magnetic resonance imaging; career; career development; computerized; design; effective intervention; experience; human old age (65+); improved; improved outcome; interhemispheric transfer; male; mortality; nerve injury; nervous system disorder; neurocognitive test; neuroimaging; neuroimaging marker; novel; novel therapeutics; pre-clinical; prevent; programs; research and development; research study; screening program; statistical learning; stem cell therapy; tool; translational scientist; white matter

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.

项目总结/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， 表情在儿童时期，大约三分之一的男孩发展为快速进展的脑ALD， 炎症和髓磷脂破坏。虽然现有的治疗方法可以阻止脑ALD的进展， 在早期发现，目前的评估不能确定哪些男孩会发展脑ALD或何时发展 它将开始。新生儿筛查计划在出生时识别ALD提供了一个机会， 避免不可逆转的神经认知能力下降的治疗方法，而新的治疗方法可能提供更安全的替代方案 标准干细胞疗法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，以测量微妙的 研究ALD儿童的大脑变化，并将这些方法应用于临床研究方案。通过指导 来自明尼苏达大学的一个专家小组，申请人提出了以下培训目标： (1)获得获取和分析神经影像学数据的知识和经验;（2）学习统计学 和新的神经认知测试的验证计算方法;（3）获得专业知识， 设计和执行临床试验。总体研究目标旨在识别早期神经认知 和脑脱髓鞘的神经影像学标志物，并加强新的临床试验的能力， 为接受早期治疗的男孩确定可靠的终点。核心假设是， 白色纤维完整性的恶化和相关的涉及体的半球间功能的丧失 胼胝体的损伤标志着脑ALD的发作，并且在MRI上出现病变之前开始。为了验证这一 假设，PI将测试几种旨在测量脱髓鞘相关变化的方法。的 特定目标将使用纵向神经认知测试（目标1）和纵向弥散MRI研究（目标2） 在患有早期疾病的男孩中确定脑ALD的功能和显微结构标记物，并检测 这些标志物的存在，在关键的前紧急阶段的风险男孩。神经认知发现 还将与疾病进展的MRI指标进行比较。这些目标的成功实现将 确定疾病发作和早期进展的可靠指标。所提出的研究是有意义的 因为检测和量化ALD男孩的细微渐进性大脑变化将允许更早地 以及更有效的干预措施来降低神经认知的发病率。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，目的是告知时间和 干预措施的有效性，以实现更好的患者结局。

项目成果

A dimensional approach to neurodevelopmental differences in genetically well-defined populations: What's next?

基因明确人群神经发育差异的维度方法：下一步是什么？

• DOI: 10.1111/dmcn.15634
• 发表时间: 2023
• 期刊: Developmental medicine and child neurology
• 影响因子: 3.8
• 作者: Pierpont,ElizabethI