Neuroimaging and Neuropathology of Mucopolysaccharidosis I

描述（由申请人提供）：我们建议研究粘多糖病I （MPS I）的神经影像学异常与神经病理学的关系，粘多糖病I是一种发生在婴儿期或儿童期的溶酶体积存病。MPS I型患儿会出现脑积水、萎缩、囊性或筛状改变以及白质异常，包括胼胝体（一种白质结构）体积减小和部分各向异性。脑积水的原因被认为是储存在蛛网膜颗粒中的脑脊液的再吸收减少，而囊性或筛状病变的原因可能是糖胺聚糖在血管周围（Virchow-Robin）间隙的积累。然而，萎缩、白质高、胼胝体（可能还有其他白质结构）体积缩小和部分各向异性的潜在基础尚不清楚。了解后这些发现的基础是很重要的，因为它们已被发现与MPS患者的认知障碍有关。我们假设成像研究中白质异常的潜在基础是髓鞘发育异常。我们在MPS I动物模型的胼胝体中发现了明显的髓鞘发育异常的证据，这与白质结构的体积减小和分数各向异性相一致。这些影像学发现背后的髓鞘异常假说将被直接检验，我们也将检验

DESCRIPTION (provided by applicant): 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.