X-LINKED ADRENOLEUKODYSTROPHY

X连锁肾上腺脑白质营养不良

• 批准号: 7602576
• 负责人: HUGO W MOSER
• 金额: $ 3.45万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602576
• 关键词: Adrenoleukodystrophy; Adrenomyeloneuropathy; Adult; Age; Biological Markers; Cervical; Cervical spinal cord structure; Clinical; Clinical Markers; Collaborations; Complement component C1s; Computer Retrieval of Information on Scientific Projects Database; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; End Point; Evaluation; Female; Fiber; Funding; Grant; Gray unit of radiation dose; Image; Imagery; Inflammatory; Institution; Link; Measures; Modality; Monitor; Myelin; Nature; Neurologic; Oils; Outcome Measure; Pathology; Patients; Phase; Phenotype; Rate; Research; Research Personnel; Resolution; Resources; Sample Size; Source; Spectrum Analysis; Spinal Cord; Spinal Cord Tract; Syndrome; Testing; Therapeutic Agents; Toes; United States National Institutes of Health; Visual; axonopathy; base; disability; dorsal column; double-blind placebo controlled trial; follow-up; in vivo; men; neuroimaging; novel therapeutics; tool; vibration; white matter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a Phase-III double blinded placebo controlled trial for Lorenzos oil treatment in 120 men with pure Adrenomyeloneuropathy and 120 symptomatic female carriers with a similar syndrome. The trial follow-up duration is for 3 years in each patient. The main aim of the trial is to test the efficacy of the Lorenzos Oil treatment in slowing disability progression in pure Adrenomyeloneuropathy (AMN) patients. Pure AMN and symptomatic female carriers represent the phenotypes of X-ALD, characterized by progressive non-inflammatory axonopathy in the long tracts of the spinal cord. Due to the non-inflammatory nature of the disease progression, visual appreciation of the spinal cord pathology using conventional imaging modalities was until recently a significant challenge. The collaboration with the resource allowed development of magnetization transfer (MT) imaging that provides high spatial resolution and sufficient SNR to distinguish gray and white matter contrast in the cervical spinal cord, allowing visualization of the dorsal column between C1 to C5 of the spinal cord at a field of 1.5 Tesla. This enabled first in vivo evaluation of the spinal cord tracts in pure AMN patients. There were significant quantitative MT differences between men with Pure AMN, symptomatic female carriers and age-matched controls. The abnormality in dorsal column correlated significantly with the dorsal column function tested by quantitatively measuring great toe vibration sensitivity threshold. Based on the initial results of our collaboration with the resource, the current trial employs quantitative modified MT evaluation of the cervical cord as a secondary outcome measure and as a tool for monitoring progression and rapidly evaluating therapy. There is no definitive treatment for neurological aspects of X-ALD. Development of sensitive quantitative biomarker is crucial for rapid evaluation of newer therapeutic agents. Current mainstay of disease evaluation is employing clinical rating scales such EDSS (Expanded Disability Status Scale), modified Rankin scale, Adult adrenoleukodystrophy scale etc. These are relatively less sensitive and require a large sample size and long follow-up to achieve adequate power for detecting significant differences in progression. To circumvent the difficulties associated with conventional clinical markers of progression, there is great emphasis on development of neuroimaging surrogates that are sensitive to ultrastructural abnormalities, specific to axonal and myelin pathology and can be reliably quantified longitudinally, for which the collaboration with the resource is essential. In collaboration with the resource, we hope to expand our neuroimaging endpoints to employ the better sensitivity of higher field as well as include diffusion tensor imaging (DTI) quantification, fiber tracking for the columns, and NAA and Cho measures for larger sections (due to the lower resolution of spectroscopy) of the cord.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这是一项针对Lorenzo的III期双盲安慰剂对照试验在120名男性患者中， 肾上腺脊髓神经病和120例有症状的女性携带者的相似综合征试验随访 每例患者的持续时间为3年。试验的主要目的是测试洛伦佐的功效的石油 在单纯肾上腺脊髓神经病（AMN）患者中，纯AMN和 有症状的女性携带者代表X-ALD的表型，其特征是进行性非炎性 脊髓长束中的轴突病。由于疾病进展的非炎症性质， 直到最近，使用常规成像方式对脊髓病理进行视觉评价， 重大挑战。与资源的合作允许开发磁化转移（MT） 提供高空间分辨率和足够SNR以区分灰度和白色物质对比度的成像 颈脊髓，允许在脊髓的C1至C5之间的背柱的视野中可视化， 1.5特斯拉这使得在纯AMN患者的脊髓束的第一个体内评价。有显著 纯AMN男性、有症状女性携带者和年龄匹配对照之间MT的定量差异。 脊髓背柱异常与脊髓背柱功能的定量测定有显著相关性 测量大脚趾振动敏感阈值。 根据我们与资源合作的初步结果，目前的试验采用了定量修改的方法， 颈髓的MT评价作为次要结局指标，并作为监测进展和 快速评估治疗。X-ALD的神经方面没有明确的治疗方法。发展 灵敏的定量生物标记物对于快速评价新的治疗剂是至关重要的。当前的支柱 疾病评估采用临床评定量表，例如EDSS（扩展残疾状态量表）、改良的兰金（Rankin 成人肾上腺脑白质营养不良量表等。这些量表的敏感性相对较低，需要大量样本， 长期随访，以获得足够的把握度来检测进展中的显著差异。规避 与传统的进展的临床标志物相关的困难，非常强调开发 神经影像学替代品，对轴突和髓鞘特有的超微结构异常敏感 病理学和可以可靠地纵向量化，为此，与资源的合作是必不可少的。在 与资源合作，我们希望扩大我们的神经成像终点，以采用更好的灵敏度， 更高场以及包括扩散张量成像（DTI）量化、柱纤维追踪和NAA 而Cho测量用于脐带的较大部分（由于光谱学的较低分辨率）。