Neuroimaging and Neuropathology of Mucopolysaccharidosis I

描述（由申请方提供）：我们拟研究神经影像学异常与粘多糖沉积症I（MPS I）神经病理学之间的关系，MPS I是一种在婴儿期或儿童期发作的溶酶体贮积病。患有MPS I的儿童出现脑积水、萎缩、囊性或筛状改变和白色物质异常，包括胼胝体（一种白色物质结构）体积减少和各向异性分数。脑积水的原因被认为是蛛网膜颗粒中储存的脑脊液的重吸收减少，而囊性或筛状病变的原因可能是血管周围（Virchow-Robin）空间中的糖胺聚糖积聚。然而，胼胝体（可能还有其他白色结构）萎缩、白色高信号、体积减少和各向异性分数降低的潜在基础尚不清楚。理解后一项发现的基础很重要，因为它们与MPS患者的认知障碍相关。我们假设白色物质异常的影像学基础是髓鞘形成障碍。我们已经发现MPS I动物模型的胼胝体中存在显著髓鞘形成障碍的证据，这与白色物质结构中的体积减小和各向异性分数一致。这些影像学发现的基础是髓鞘形成障碍的假设将被直接检验，我们还将检验 灰质疾病或脑积水是原因的另一种假设。所采用的方法包括高分辨率磁共振成像、体积测量、扩散张量成像、白色和灰质的超微结构研究、髓鞘成分的评价以及灰质和白色物质病理学的其他评价。测试的干预措施将包括在青少年时期使用鞘内酶替代疗法治疗和脑积水的脑室腹膜分流术。结果将导致一个新的，中央模型，以连接神经病理学和神经影像学发现，这是理解多磺酸粘多糖相关脑疾病发病机制的关键。

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.