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: 10649537
• 负责人: Eric Mallack
• 金额: $ 19.43万
• 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/10649537
• 关键词: 18 year old; Adolescent; Adrenoleukodystrophy; Adult; Affect; Age; Anisotropy; Appearance; Architecture; Autopsy; Biology; Biometry; Brain; Cerebrum; Cessation of life; Child; Childhood; Consensus; Corpus Callosum; Data; Demyelinating Diseases; Demyelinations; Development; 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; Multiple Sclerosis; Mutation; Myelin; Neonatal Screening; Nerve Degeneration; Neurocognitive Deficit; Neurodevelopmental Disorder; Neurologic; Neurologic Symptoms; Neurological outcome; Pathogenesis; Pathologic; Patient Care; Patients; Prevention strategy; Procedures; Process; Publishing; Research Personnel; Site; Structural defect; Techniques; Testing; Time; Training; Translating; Vegetative States; Very Long Chain Fatty Acid; Water; White Matter Disease; Work; biomarker development; boys; career development; clinical application; extracellular; imaging biomarker; in vivo; infancy; inter-institutional; leukodystrophy; longitudinal analysis; medical schools; mortality; nervous system disorder; neurogenetics; neuroimaging; pediatric patients; post-transplant; skills; validation studies; 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连锁的肾上腺素肌营养不良（ALD）是由突变引起的毁灭性神经系统疾病 ABCD1基因。估计的疾病发生率为1/17,000，但是最近的新生儿机构 筛选显示出明显更高的速度。大多数患者将发展大脑ALD（CALD）， 在童年时期发生的发病率最高。大多数患者随后发生炎症性脱髓鞘 通过2至3年的神经变性和死亡。造血干细胞移植（HSCT）是最有效的 当神经系统症状发作之前，在狭窄的窗户中启动时。有一个明确指出的 需要采取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，提供可能的预防策略，从而有助于最大化 神经学结果。总体脂质含量降低，增加髓磷脂非常长的链脂肪酸脂质 分数和髓磷脂含量降低是CALD的最早的病理变化 脱髓鞘。扩散张量（DTI）和髓磷脂水分（MWF）成像是先进的，体内 特定于本地纤维架构和髓磷脂水含量的方式。马拉克博士假设 DTI可以检测到髓磷脂发育期间早期CALD的异常微观结构变化 和MWF在发作和/或脱髓鞘进展之前。 Mallack博士将通过 调查单个白质的发展（AIM 1），病变发作和进展（AIM 2）， 患有CALD，无症状半合子和对照的小儿患者。如果他的假设是 经本研究验证，该方法将（1）确认CALD患者的正常髓磷脂发育，（2） 与预期的白质的区域特定区域，特定于区域的逆转倒置较早CALD 曲线，（3）为早期疾病监测提供了一种敏感的方式，（4）有助于预测患者 适合治疗。 通过实现这些目标，Mallack博士将接受富裕的机构间指导，由Florian Eichler博士。 马萨诸塞州综合医院的白细胞营养不良的世界专家和Sumit Niogi博士 威尔·康奈尔医学院（Weill Cornell Medical College）高级神经影像学。此外，Mallack博士将由团队指导 具有神经遗传疾病的互补专业知识，高级成像生物标志物发展和 调查和生物统计学。除了他的职业发展活动外，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 研究者。这将解决他（1）使用高级成像技术探测基础的目标 遗传白质疾病的生物学，以及（2）将尖端图像分析转化为临床应用， 从而推进受这些破坏性疾病影响的患者的护理。

项目成果

Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy.

• DOI: 10.3390/cells11020283
• 发表时间: 2022-01-14
• 期刊: Cells
• 影响因子: 6
• 作者: Mallack EJ;Gao K;Engelen M;Kemp S
• 通讯作者: Kemp S

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

• DOI: 10.1212/wnl.0000000000201374
• 发表时间: 2022-11-22
• 期刊: NEUROLOGY
• 影响因子: 9.9
• 作者: Engelen, Marc;Van Ballegoij, Wouter J. C.;Mallack, Eric James;Van Haren, Keith P.;Kohler, Wolfgang;Salsano, Ettore;Van Trotsenburg, A. S. P.;Mochel, Fanny;Sevin, Caroline;Regelmann, Molly O.;Tritos, Nicholas A.;Halper, Alyssa;Lachmann, Robin H.;Davison, James;Raymond, Gerald V.;Lund, Troy C.;Orchard, Paul J.;Kuehl, Joern-Sven;Lindemans, Caroline A.;Caruso, Paul;Turk, Bela Rui;Moser, Ann B.;Vaz, Frederic M.;Ferdinandusse, Sacha;Kemp, Stephan;Fatemi, Ali;Eichler, Florian S.;Huffnagel, Irene C.
• 通讯作者: Huffnagel, Irene C.

Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy.

• DOI: 10.1016/j.ebiom.2023.104781
• 发表时间: 2023-10
• 期刊: EBioMedicine
• 影响因子: 11.1