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

摘要 X-连锁肾上腺脑白质营养不良（ALD）是一种破坏性的神经系统疾病， ABCD 1基因。估计发病率为1/17，000，但最近新生儿 筛查显示发病率明显较高。大多数患者会发展为脑ALD（CALD）， 儿童期发病率最高。大多数患者发生炎性脱髓鞘， 神经退化和死亡。造血干细胞移植（HSCT）最有效 当在神经症状发作之前的窄窗口内开始时。有明确规定的 需要更敏感的措施来检测病变的发作和进展。CALD的早期诊断将扩大 治疗窗口为可能的预防策略提供了准备时间，从而有助于最大化 神经学结果。总体脂质含量降低，髓鞘极长链脂肪酸脂质增加 髓鞘水含量的减少是CALD最早的病理变化， 脱髓鞘扩散张量（DTI）和髓鞘水分数（MWF）成像是先进的，在体内 局部纤维结构和髓鞘水含量的特定模式。Mallack博士假设 DTI可以检测到早期CALD在髓鞘发育过程中的异常显微结构变化 以及在脱髓鞘发生和/或进展之前的MWF。Mallack博士将测试这个假设， 研究个体白色物质束发育（目标1）和病变发作和进展（目标2）， 发生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）证实CALD患者的髓鞘发育正常，（2） 将早期CALD重新定义为与预期的白色物质道成熟的区域性、特定道的分歧 曲线，（3）为早期疾病监测提供灵敏的模式，（4）有助于预测患者 适合治疗。 通过实现这些目标，Mallack博士将接受Florian Eichler博士的丰富的机构间指导， 马萨诸塞州总医院的世界脑白质营养不良专家Sumit Niogi博士和 高级神经影像学，在威尔康奈尔医学院。此外，马拉克博士将由一个团队 在神经遗传性疾病、先进的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，Mallack博士的委员会 导师，合作者和顾问将促进他的发展和过渡到独立的 调查员这将解决他的目标（1）使用先进的成像技术来探测潜在的 遗传性白色疾病的生物学，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。

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.