Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome
Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome
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DOI：
10.1073/pnas.1002762107
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发表时间：
2010-05-18
影响因子：
11.1
通讯作者：
Reiss, Allan L.
中科院分区：
文献类型：
--
作者：
Hoeft, Fumiko;Carter, John C.;Reiss, Allan L.
脆性X综合征（FXS）是遗传性智力残疾和自闭症的最常见原因，其纵向神经影像学研究为研究特定遗传因素对活体人脑神经发育的影响提供了机会。我们在2年的时间里检查了1至3岁FXS男孩（n = 41）的体素灰色和白色物质体积（GMV，WMV），并将这些结果与年龄和发育匹配的对照组（n = 28）进行了比较。我们发现在这两个时间点FXS的尾状核，丘脑，梭状回和小脑蚓部的GMV增加和减少，提示早期，可能是产前，神经发育的遗传介导的改变。相比之下，区域中，初始GMV是相似的，其次是一个改变的生长轨迹，导致FXS的大小增加，如眶回，基底前脑，丘脑，表明延迟或以其他方式中断突触修剪发生产后。与对照组相比，FXS组纹状体-前额区的WMV更大，随着时间的推移，组间差异变得更加夸张，表明这种WM异常可能是原发性FMRP缺乏相关轴突病理的结果，而不是形态学上非典型脑结构之间的继发性连接失调。我们的研究结果表明，FXS中不同脑区的结构异常随着时间的推移而发生不同的变化，反映了FMRP缺乏的时间依赖性影响，并提供了对其神经病理基础的深入了解。在人类中创建FXS的早期和准确的人脑表型将显着提高我们检测新的疾病特异性治疗是否可以“拯救”受影响个体的FXS表型的能力。
Longitudinal neuroimaging investigation of fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, provides an opportunity to study the influence of a specific genetic factor on neurodevelopment in the living human brain. We examined voxel-wise gray and white matter volumes (GMV, WMV) over a 2-year period in 1- to 3-year-old boys with FXS (n = 41) and compared these findings to age-and developmentally matched controls (n = 28). We found enlarged GMV in the caudate, thalamus, and fusiform gyri and reduced GMV in the cerebellar vermis in FXS at both timepoints, suggesting early, possibly prenatal, genetically mediated alterations in neurodevelopment. In contrast, regions in which initial GMV was similar, followed by an altered growth trajectory leading to increased size in FXS, such as the orbital gyri, basal forebrain, and thalamus, suggests delayed or otherwise disrupted synaptic pruning occurring postnatally. WMV of striatal-prefrontal regions was greater in FXS compared with controls, and group differences became more exaggerated over time, indicating the possibility that such WM abnormalities are the result of primary FMRP-deficiency-related axonal pathology, as opposed to secondary connectional dysregulation between morphologically atypical brain structures. Our results indicate that structural abnormalities of different brain regions in FXS evolve differently over time reflecting time-dependent effects of FMRP deficiency and provide insight into their neuropathologic underpinnings. The creation of an early and accurate human brain phenotype for FXS in humans will significantly improve our capability to detect whether new disease-specific treatments can "rescue" the FXS phenotype in affected individuals.