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)是一种毁灭性的神经疾病，由基因突变引起 ABCD1基因。估计发病率为1/17,000，然而，最近的新生儿机构 筛查显示，这一比例要高得多。大多数患者会发展为脑性阿尔茨海默病(CALD)， 发病率最高的是儿童时期。大多数患者随后会经历炎性脱髓鞘 由神经变性和死亡在2到3年内。造血干细胞移植是最有效的 当在神经系统症状出现之前的狭窄窗口启动时。有一个明确规定的 需要更灵敏的措施来检测病变的发生和发展。CALD的早期诊断将扩大 治疗窗口，为可能预防策略提供准备时间，从而帮助最大限度地 神经学结果。降低总脂肪含量，增加髓鞘极长链脂肪酸脂 部分和髓鞘水含量减少是CALD最早的病理改变，在此之前 脱髓鞘。扩散张量成像(DTI)和髓鞘水组分(MWF)成像在体内是先进的 特定于局部纤维结构和髓鞘水分含量的模式。Mallack博士假设 DTI可检测早期CALD髓鞘发育过程中的微结构异常改变 和MWF在脱髓鞘开始和/或进展之前。Mallack博士将通过以下方式检验这一假设 研究个体白质束发育(目标1)和病变的发生和进展(目标2)，#年 发生CALD、无症状半合子和对照组的儿科患者。如果他的假设是 通过这项研究验证，该方法将(1)证实CALD患者髓鞘发育正常，(2) 将早期CALD重新定义为区域性的、特定于区域的、与预期的白质束成熟的背离 曲线，(3)为早期疾病监测提供一种灵敏的方式，以及(4)帮助预测患者 适合治疗的。 通过实现这些目标，Mallack博士将得到弗洛里安·艾希勒博士丰富的机构间指导。 马萨诸塞州总医院的世界白质营养不良专家和苏米特·尼奥吉博士，他是 威尔·康奈尔医学院的高级神经成像。此外，Mallack博士将由一个团队指导 在神经遗传疾病、先进的成像生物标记物开发和 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并过渡到独立的 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 遗传性白质病的生物学，以及(2)将尖端图像分析转化为临床应用， 从而促进了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.