A voxel-based morphometry study of grey matter loss in fragile X-associated tremor/ataxia syndrome
A voxel-based morphometry study of grey matter loss in fragile X-associated tremor/ataxia syndrome
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DOI：
10.1093/brain/awq368
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发表时间：
2011-03-01
期刊：
影响因子：
14.5
通讯作者：
Rivera, Susan M.
中科院分区：
文献类型：
--
作者：
Hashimoto, Ryu-ichiro;Javan, Alireza K.;Rivera, Susan M.
脆性X相关震颤/共济失调综合征是一种神经退行性疾病，主要影响脆性X智力低下基因的老年男性前突变携带者。虽然其核心症状主要表现为意向震颤和步态共济失调等运动问题，但认知能力下降和精神问题也很常见。过去的放射学和组织学方法主要集中在特定大脑结构中显著的神经退行性改变，包括小脑和边缘区域。然而，对局部结构异常的定量研究尚未覆盖整个大脑。在这项研究中，我们采用了基于体素的形态计量学方法和小脑感兴趣区分析相结合的方法，研究了患有和不患有脆性X相关震颤/共济失调综合征的男性前突变携带者的局部灰质变化模式。在与健康对照组的比较中，我们发现脆性X相关震颤/共济失调综合征患者皮质和皮质下结构的多个区域有显著的灰质丢失。在小脑，前叶和上后叶在前额叶和大脑半球均有明显缩小。在大脑皮质，在大脑内侧表面的延伸区，包括背内侧前额叶皮质、前扣带回皮质和楔前叶，发现非常显著的灰质减少簇。另一个突出的灰质丢失出现在外侧前额叶皮质、眶前叶皮质、杏仁核和脑岛。尽管无症状前突变组和健康对照组之间的体素水平比较没有达到显著差异，但感兴趣区分析显示，无症状前突变组小脑前部和大脑半球灰质显著减少。使用行为量表对前突变组进行的相关分析表明，左侧杏仁核灰质丢失与强迫症和抑郁水平的增加，以及左下额叶皮质和前扣带皮质灰质减少与工作记忆能力低下之间存在显著关联。此外，回归分析显示CGG重复大小对额背内侧灰质密度有显著的负面影响。部分疣体与脆性X相关震颤/共济失调综合征的严重程度与临床评分呈显著负相关。这些观察揭示了脆性X相关震颤/共济失调综合征运动、认知和精神问题背后的神经退化过程的解剖模式，以及在该疾病临床发病之前可能发生的早期结构异常。
Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disorder that primarily affects older male premutation carriers of the fragile X mental retardation gene. Although its core symptoms are mainly characterized by motor problems such as intention tremor and gait ataxia, cognitive decline and psychiatric problems are also commonly observed. Past radiological and histological approaches have focused on prominent neurodegenerative changes in specific brain structures including the cerebellum and limbic areas. However, quantitative investigations of the regional structural abnormalities have not been performed over the whole brain. In this study, we adopted the voxel-based morphometry method together with regions of interest analysis for the cerebellum to examine the pattern of regional grey matter change in the male premutation carriers with and without fragile X-associated tremor/ataxia syndrome. In a comparison with healthy controls, we found striking grey matter loss of the patients with fragile X-associated tremor/ataxia syndrome in multiple regions over the cortical and subcortical structures. In the cerebellum, the anterior lobe and the superior posterior lobe were profoundly reduced in both vermis and hemispheres. In the cerebral cortex, clusters of highly significant grey matter reduction were found in the extended areas in the medial surface of the brain, including the dorsomedial prefrontal cortex, anterior cingulate cortex and precuneus. The other prominent grey matter loss was found in the lateral prefrontal cortex, orbitofrontal cortex, amygdala and insula. Although the voxel-wise comparison between the asymptomatic premutation group and healthy controls did not reach significant difference, a regions of interest analysis revealed significant grey matter reduction in anterior subregions of the cerebellar vermis and hemisphere in the asymptomatic premutation group. Correlation analyses using behavioural scales of the premutation groups showed significant associations between grey matter loss in the left amygdala and increased levels of obsessive-compulsiveness and depression, and between decreased grey matter in the left inferior frontal cortex and anterior cingulate cortex and poor working memory performance. Furthermore, regression analyses revealed a significant negative effect of CGG repeat size on grey matter density in the dorsomedial frontal regions. A significant negative correlation with the clinical scale for the severity of fragile X-associated tremor/ataxia syndrome was found in a part of the vermis. These observations reveal the anatomical patterns of the neurodegenerative process that underlie the motor, cognitive and psychiatric problems of fragile X-associated tremor/ataxia syndrome, together with incipient structural abnormalities that may occur before the clinical onset of this disease.