INTERNET MULTICENTER THERAPEUTIC TRIALS OF X LINKED ADRENOLEUKODYSTROPHY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。Moser博士的研究项目主要涉及x -连锁肾上腺脑白质营养不良症（X-ALD），并涉及该疾病的各个方面，从分子生物学到动物模型，临床诊断和治疗方案。我们的实验室已经关注这种疾病超过20年，已经鉴定了5000多名患者，被认为是研究和治疗X-ALD的国内和国际资源。MRI和MRS对于X-ALD的诊断至关重要，对于该疾病的患者和小鼠模型的发病机制的基础研究也至关重要，此外，对于决定治疗干预措施及其评估也是绝对必要的。X-ALD引起脱髓鞘和轴突损伤，导致进行性神经功能障碍并最终死亡。由于表型表达的显著和不可预测的变化，它提出了诊断和治疗的挑战。其表型范围从导致完全残疾并常常在10岁前死亡的幼年脑型，到轻度的成年型，在另一个极端可能与生存相容，到80岁只有中度残疾。不同的表型通常同时发生在同一个家族中，与突变的性质或生化缺陷的严重程度无关。MRI和MRS已被发现是临床病程和治疗评价的最有效的预测指标。MRI异常常显示特征性模式。脑MRI异常先于神经系统症状的发展。我们实验室的研究表明，核磁共振是一种更敏感的神经系统病变预测器。Pouwels等人最近的研究表明，聚焦于胆碱和肌醇峰的定量光谱有助于确定脱髓鞘是处于活跃阶段还是静止阶段，这些方法现在正在f.m.k irby中心得到应用和推广。你们资源项目2中正在开发的MR光谱技术的进步对这个项目至关重要。在临床水平上，MRI和MRS对于决定患者是否应该接受骨髓移植至关重要。这种手术在仔细定义的情况下是有效的，但风险很高，不应该提供给不需要它的患者，或者太残疾而无法从中受益的患者。最近的进展，包括MRS和磁化转移技术对这一决定至关重要。我们在10月1日提交的申请中要求FDA和NIH资助的多中心临床试验支持的研究涉及治疗干预的评估。核磁共振成像和MRS是这些评估的关键，将通过与国家医学图书馆的合同得到极大的协助。在这份合同中，“下一代互联网”将用于将来自世界各地的图像传输到F.M.柯比中心，并在柯比中心对图像进行评估。除了这些临床应用外，项目2还将用于加深对患者X-ALD发病机制的了解。这些发病机制的研究将包括与神经病理和神经生理改变的比较，以及对BMT和药物治疗效果的检查。除了MRS之外，本研究还将使用TRD3中开发的方法进行连通性测试。Mori等人最近发表的论文（MRM 2002）显示了第一个结果。

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. Dr Moser's research programs relate mainly to X-Linked Adrenoleukodystrophy (X-ALD) and concern all aspects of this disorder, ranging from molecular biology, to animal models, clinical diagnosis, and therapeutic protocols. Our laboratory has been concerned with this disease for more than twenty years, has identified more than five thousand patients, and is considered a national and international resource for the study and therapy of X-ALD. MRI and MRS are crucial for the diagnosis of X-ALD, and also for basic studies of pathogenesis, both in patients and in a mouse model of this disease, and in addition are absolutely essential to decisions about therapeutic interventions and to their evaluation. X-ALD causes demyelination and axonal damage, which lead to progressive neurological disability and eventually to death. It presents diagnostic and therapeutic challenges because of striking and unpredictable variations in phenotypic expression. The phenotype ranges fr om the chi ldhood cerebral form which leads to total disability and often to death by ten years of age, to milder adult forms, which at the other extreme may be compatible with survival to the eight's decade with only moderate disability. The various phenotypes often co-occur in the same family and do not correlate with the nature of the mutation or the severity of the biochemical deficit. MRI and MRS have been found to be the most valid predictors of clinical course and the evaluation of therapy. The MRI abnormalities often shown characteristic patterns. Brain MRI abnormalities precede the development of neurological symptoms. Studies in our lab have shown that MRS is an even more sensitive predictor of neurological involvement. Recent studies by Pouwels et al. indicate that quantitative spectroscopy with focus on the choline and myoinositol peaks help to determine whether demyelination is in an active or quiescent stage, and these approaches are now being utilized and extended at the F.M. K irby Center. The advances in MR spectroscopy techniques, being developed in Project 2 of your Resource are of critical importance to this program. At the clinical level MRI and MRS are essential for the decision whether a patient should receive a bone marrow transplant. This procedure is effective under carefully defined circumstances, but carries a high risk and should not be offered to patients who do not need it, or are too disabled to benefit from it. Recent advances, including MRS and magnetization transfer techniques are of key importance to this decision. The study supported by the FDA and the Multicenter Clinical Trial for which NIH funding for is requested in our application to be submitted on October 1, involve the evaluation of therapeutic interventions. MRI and MRS are key to these evaluations and will be assisted greatly through the Contract with the National Library of Medicine. In this contract the "next generation internet" will be utilized to transmit images from all parts of the world to the F.M. Kirby Center, where they will be evaluated in the Kirby Center. In addition to these clinically oriented applications, Project 2 will be applied to enhance understanding of the pathogenesis of X-ALD in patients. These studies of pathogenesis will include comparisons with neuropathological and neurophysiological alterations as well as examination of the effects of BMT and pharmacological therapies. In addition to MRS, the present studies will also employ connectivity testing using the methodology developed in TRD3. A first result was shown in the recent paper by Mori et al., MRM 2002.