Neuroimaging and Neuropathology of Mucopolysaccharidosis I

项目摘要/摘要 我们建议研究神经影像异常与神经病理的关系。 粘多糖I型(MPS I)，一种溶酶体储积性疾病，发病于婴幼儿或儿童时期。儿童 在MPS中，我会出现脑积水、萎缩、囊状或筛状改变以及脑白质异常。 包括胼胝体体积减小和各向异性分数(白质结构)。这个 脑积水的原因被认为是由于脑脊液在脑脊液中储存的重吸收减少 蛛网膜下腔肉芽肿，囊性或筛状病变的原因可能是积聚的 血管周围(Virchow-Robin)间隙中的糖胺聚糖。然而，萎缩的根本基础是白色 物质的高信号、体积减小和部分各向异性(很可能 其他白质结构)是未知的。理解后面这些发现的基础是很重要的， 因为已经发现它们与MPS患者的认知障碍相关。我们假设 脑白质异常的基础是影像研究中的髓鞘异常。我们找到了证据 在MPS I动物模型中显示出显著的髓鞘异常，这与 白质结构中体积减小和各向异性分数。关于髓鞘功能障碍的假设 在这些成像发现的基础上，我们将直接测试，我们还将测试灰色的替代假设 物质疾病或脑积水是责任所在。所采用的方法将包括高分辨率磁力 磁共振成像，体积测量，扩散张量成像，白质和灰质的超微结构研究， 髓鞘成分的评估，以及灰质和白质病理的其他评估。干预措施 测试将包括在幼年期使用鞘内酶替代疗法和 脑室-腹膜分流术治疗脑积水结果将导致一个新的中心模型来连接 神经病理和神经影像表现是了解MPS发病机制的关键。 相关的脑部疾病。

PROJECT SUMMARY/ABSTRACT We propose to study the relationship of neuroimaging abnormalities and neuropathology in mucopolysaccharidosis I (MPS I), a lysosomal storage disease that strikes in infancy or childhood. Children with MPS I develop hydrocephalus, atrophy, cystic or cribriform changes, and white matter abnormalities including decreased volume and fractional anisotropy of the corpus callosum (a white matter structure). The cause of hydrocephalus is thought to be decreased reabsorption of cerebrospinal fluid from storage in the arachnoid granulations, and the cause of cystic or cribriform lesions is probably the accumulation of glycosaminoglycans in perivascular (Virchow-Robin) spaces. However, the underlying basis of atrophy, white matter hyperintensities, and reduced volume and fractional anisotropy in the corpus callosum (and probably other white matter structures) is not known. The basis of these latter findings is important to understand, because they have been found to correlate with cognitive impairment in MPS patients. We hypothesize that the underlying basis of white matter abnormalities on imaging studies is dysmyelination. We have found evidence of significant dysmyelination in the corpus callosum of an MPS I animal model which is consistent with the reduced volume and fractional anisotropy in that white matter structure. The hypothesis that dysmyelination underlies these imaging findings will be directly tested, and we will also test alternate hypotheses that gray matter disease or hydrocephalus is responsible. Methods employed will include high-resolution magnetic resonance imaging, volumetrics, diffusion tensor imaging, ultrastructural studies of white and gray matter, evaluations of myelin components, and other evaluations of gray and white matter pathology. Interventions tested will include treatment with intrathecal enzyme replacement therapy in the juvenile period and ventriculoperitoneal shunting for hydrocephalus. The results will lead to a new, central model to connect neuropathology and neuroimaging findings, which are the key to understanding the pathogenesis of MPS- related brain disease.