Neuroimaging and Neuropathology of Mucopolysaccharidosis I

描述(申请人提供)：我们建议研究粘多糖病I(MPS I)的神经影像异常与神经病理学的关系，MPS I是一种发生在婴幼儿或儿童时期的溶酶体储存性疾病。患有MPS I的儿童会出现脑积水、萎缩、囊状或筛状改变，以及脑白质异常，包括体积减小和胼胝体(白质结构)的各向异性。脑积水的原因被认为是储存在蛛网膜颗粒中的脑脊液重吸收减少，囊状或筛状病变的原因可能是糖胺聚糖在血管周围(Virchow-Robin)腔内积聚。然而，胼胝体(可能还有其他白质结构)萎缩、白质高信号、体积减小和各向异性分数的潜在基础尚不清楚。理解后一项发现的基础是重要的，因为它们已被发现与MPS患者的认知损害相关。我们假设在影像研究中白质异常的潜在基础是髓鞘异常。我们在MPS I动物模型中发现了明显的髓鞘障碍的证据，这与白质结构中体积减小和各向异性分数相一致。这些成像结果背后的髓鞘异常的假设将被直接测试，我们也将测试 另一种假设是灰质疾病或脑积水。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。测试的干预措施将包括在幼年期进行鞘内酶替代治疗和脑室-腹膜分流术治疗脑积水。这一结果将导致一个新的中央模型，将神经病理学和神经成像结果联系起来，这是理解MPS相关脑部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.