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: 10524184
• 负责人: Elizabeth Irene Pierpont
• 金额: $ 15.87万
• 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/10524184
• 关键词: 10 year old; Adrenal gland hypofunction; Adrenoleukodystrophy; Adrenomyeloneuropathy; Affect; Age; 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 treatment; Encephalitis; Fiber; Fingers; Foundations; Funding; Future; Goals; Guidelines; Hematopoietic Stem Cell Transplantation; Individual; Informal Social Control; Investigation; Investigational Therapies; K-Series Research Career Programs; Knowledge; Lead; Lesion; Link; Magnetic Resonance Imaging; Measures; Mentorship; Methodology; Methods; Minnesota; Modality; Monitor; Morbidity - disease rate; Myelin; Neonatal Screening; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Onset of illness; Outcome; Pathogenicity; Patient-Focused Outcomes; Patients; Protocols documentation; Public Health; 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; 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.

项目概要/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，其变化不可预测。 表达。在童年时期，大约三分之一的男孩会出现快速进展的大脑 ALD 炎症和髓磷脂破坏。尽管现有的治疗方法可以阻止脑 ALD 的进展 在早期发现，目前没有评估可以确定哪些男孩会患上脑性酒精性肝病，或者何时会患上脑性酒精性肝病 它将开始。在出生时识别 ALD 的新生儿筛查计划提供了更早提供服务的机会 避免不可逆转的神经认知衰退的治疗，而新的治疗可能提供更安全的替代方案 标准干细胞治疗。 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微妙的 患有 ALD 的儿童的大脑变化，并将这些方法应用于临床研究方案。有指导 根据明尼苏达大学专家团队的要求，申请人提出以下培训目标： (1) 获得神经影像数据采集和分析的知识和经验； (2)学习统计 以及用于验证新型神经认知测试的计算方法； (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标志物，并增强新药物的临床试验能力 为接受早期治疗的男孩定义稳健的终点疗法。中心假设是 白质纤维完整性恶化以及相关的大脑半球间功能丧失 胼胝体标志着脑 ALD 的发生，并且在 MRI 出现病变之前开始。为了测试这个 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 具体目标将使用纵向神经认知测试（目标 1）和纵向扩散 MRI 研究（目标 2） 鉴定早期疾病男孩脑 ALD 的功能和微观结构标志物，并测试 在高危男孩的关键的芽前阶段，这些标记物的存在。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。拟议的研究意义重大 因为对患有 ALD 的男孩进行性大脑细微变化的检测和量化将有助于更早地发现 以及更有效的干预措施以降低神经认知发病率。培训目标将支持 申请人的职业目标是领导一项识别大脑敏感标记的长期研究计划 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，以实现更好的患者治疗效果。