Leveraging myelin-sensitive imaging to predict early lesion pathogenesis in cerebral adrenoleukodystrophy

利用髓磷脂敏感成像预测脑肾上腺脑白质营养不良的早期病变发病机制

• 批准号: 10301855
• 负责人: Eric Mallack
• 金额: $ 19.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301855
• 关键词: 18 year old; Address; Adolescent; Adrenoleukodystrophy; Affect; Age; Anisotropy; Appearance; Architecture; Autopsy; Biology; Biometry; Brain; Cerebrum; Cessation of life; Child; Childhood; Consensus; Corpus Callosum; Data; Demyelinating Diseases; Demyelinations; Development; Diffuse; Diffusion; Disease; Disease Progression; Early Diagnosis; Early Intervention; Early identification; Encephalitis; Fiber; Functional disorder; General Hospitals; Genes; Genetic; Goals; Growth; Hematopoietic Stem Cell Transplantation; Histologic; Histopathology; Image; Image Analysis; Imaging Techniques; Incidence; Individual; Inflammatory; Injury; Institution; Investigation; Lead; Lesion; Lipids; Literature; Magnetic Resonance Imaging; Massachusetts; Measurement; Measures; Mentors; Mentorship; Minority; Modality; Modeling; Monitor; Morbidity - disease rate; Mutation; Myelin; Neonatal Screening; Nerve Degeneration; Neurocognitive Deficit; Neurologic; Neurologic Symptoms; Neurological outcome; Pathogenesis; Pathologic; Patient Care; Patients; Prevention strategy; Procedures; Process; Publishing; Research Personnel; Site; Structural defect; Structure; Techniques; Testing; Time; Training; Translating; Vegetative States; Very Long Chain Fatty Acid; Water; White Matter Disease; Work; base; biomarker development; boys; career development; clinical application; extracellular; imaging biomarker; in vivo; infancy; inter-institutional; leukodystrophy; longitudinal analysis; medical schools; nervous system disorder; neurogenetics; neuroimaging; pediatric patients; post-transplant; skills; white matter

ABSTRACT X-linked Adrenoleukodystrophy (ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene. The estimated incidence of disease is 1/17,000, however the recent institution of newborn screening has revealed significantly higher rates. The majority of patients will develop cerebral ALD (CALD), with the highest incidence occurring in childhood. Most patients undergo inflammatory demyelination followed by neurodegeneration and death in 2 to 3 years. Hematopoietic Stem Cell Transplant (HSCT) is most effective when initiated in the narrow window prior to the onset of neurological symptoms. There is an explicitly stated need for more sensitive measures to detect lesion onset and progression. Early diagnosis of CALD will widen the treatment window, provide lead-time for possible preventative strategies, and thereby help maximize neurological outcomes. Decreased overall lipid content, increase in myelin very long chain fatty acid lipid fractions, and decrease in myelin water content are the earliest pathological changes in CALD, prior to demyelination. Diffusion Tensor (DTI) and Myelin Water Fraction (MWF) Imaging are advanced, in vivo modalities specific to local fiber architecture and myelin water content. Dr. Mallack hypothesizes that abnormal microstructural changes in early CALD during myelin development can be detected by DTI and MWF prior to the onset and/or progression of demyelination. Dr. Mallack will test this hypothesis by investigating individual white matter tract development (Aim 1), and lesion onset and progression (Aim 2), in pediatric patients who developed CALD, asymptomatic hemizygotes, and controls. If his hypotheses are validated by this study, the approach will (1) confirm normal myelin development in patients with CALD, (2) reframe early CALD as a regional, tract-specific, divergence from the expected white matter tract maturational curve, (3) provide a sensitive modality for early disease monitoring, and (4) aid in prediction of patients appropriate for therapy. By achieving these aims, Dr. Mallack will undergo rich inter-institutional mentorship by Dr. Florian Eichler, a world expert in the leukodystrophies, at Massachusetts General Hospital and Dr. Sumit Niogi, a leader in advanced neuroimaging, at Weill Cornell Medical College. Additionally, Dr. Mallack will be guided by a team with complementary expertise in neurogenetic disorders, advanced imaging biomarker development and investigation, and biostatistics. In addition to his career development activities, Dr. Mallack's committee of mentors, collaborators, and advisors will promote his development and transition to an independent investigator. This will address his goals of (1) using advanced imaging techniques to probe the underlying biology of genetic white matter disease, and (2) translate cutting-edge image analyses into clinical applications, thereby advancing the care of patients affected by these devastating disorders.

抽象的 X连锁肾上腺脑白质营养不良（ALD）是一种毁灭性的神经系统疾病，由基因突变引起 ABCD1 基因。估计疾病发病率为 1/17,000，然而最近的新生儿机构 筛查显示比率明显更高。大多数患者会发展为脑性酒精性肝病（CALD）， 其中发生率最高的是儿童期。大多数患者随后会发生炎症性脱髓鞘 神经退行性变并在 2 至 3 年内死亡。造血干细胞移植（HSCT）是最有效的 当在神经系统症状出现之前的狭窄窗口内启动时。有明确规定 需要更灵敏的措施来检测病变的发生和进展。 CALD 的早期诊断范围将扩大 治疗窗口，为可能的预防策略提供准备时间，从而帮助最大限度地提高 神经学结果。总体脂质含量降低，髓磷脂超长链脂肪酸脂质增加 分数和髓磷脂水含量的减少是 CALD 中最早的病理变化，先于 脱髓鞘。先进的体内弥散张量 (DTI) 和髓磷脂水分数 (MWF) 成像 特定于局部纤维结构和髓磷脂水含量的模式。 Mallack 博士假设 DTI 可检测髓磷脂发育过程中早期 CALD 的异常微观结构变化 和 MWF 在脱髓鞘发生和/或进展之前。 Mallack 博士将通过以下方式检验这一假设： 研究个体白质束的发育（目标 1）以及病变的发生和进展（目标 2） 出现 CALD 的儿科患者、无症状半合子和对照。如果他的假设是 经本研究验证，该方法将 (1) 确认 CALD 患者髓磷脂发育正常，(2) 将早期 CALD 重新定义为区域性的、特定于脑束的、与预期白质束成熟的分歧 曲线，(3) 为早期疾病监测提供灵敏的方式，(4) 帮助预测患者 适合治疗。 为了实现这些目标，Mallack 博士将接受 Florian Eichler 博士的丰富的机构间指导。 麻省总医院脑白质营养不良领域的世界专家和脑白质营养不良领域的领导者 Sumit Niogi 博士 威尔康奈尔医学院的高级神经影像学。此外，马拉克博士将由一个团队指导 具有神经遗传疾病、先进成像生物标志物开发和 调查和生物统计学。除了他的职业发展活动之外，马拉克博士的委员会 导师、合作者和顾问将促进他的发展和向独立的过渡 研究者。这将实现他的目标：(1) 使用先进的成像技术来探测底层 遗传性白质疾病的生物学，以及（2）将尖端图像分析转化为临床应用， 从而促进对受这些破坏性疾病影响的患者的护理。