Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia
Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia
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DOI：
10.1212/01.wnl.0000267844.72421.6c
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发表时间：
2007-08-28
期刊：
影响因子：
9.9
通讯作者：
Klein, C.
中科院分区：
文献类型：
--
作者：
Binkofski, F.;Reetz, K.;Klein, C.
背景：Parkin和PINK 1基因突变可导致帕金森综合征。由于帕金或PINK 1基因的单个突变等位基因的无症状携带者显示纹状体中的突触前多巴胺能功能障碍，因此它们提供了一种独特的体内模型来研究响应于潜伏性黑质纹状体功能障碍的结构和功能重组。我们假设由这些突变引起的亚临床黑质纹状体神经变性会诱导功能障碍的纹状体灰质的形态学变化。在杂合Parkin（n = 13）或PINK 1（n = 10）突变的无症状携带者和23名年龄和性别匹配的无突变个体中，我们将观察者独立的感兴趣区域和基于体素的形态测量应用于高分辨率结构MRI。结果：相对于没有突变的对照组，Parkin和PINK 1突变携带者显示出壳核和内部苍白球灰质体积的双侧增加。在13例Parkin突变携带者中的8例中，用F-18-DOPA PET研究了突触前多巴胺能功能。代谢-形态计量回归分析显示，单个突触前纹状体F-18-DOPA摄取的线性减少与双侧壳核和左侧尾状核中纹状体灰质体积的相互减少有关。纹状体灰质体积增加的另一个原因可能是由于慢性多巴胺能功能障碍引起的神经元活动过度，或者由于长期的多巴胺能功能障碍引起的神经元活动过度。长期适应慢性黑质纹状体功能障碍，积极补偿多巴胺能去神经支配。在任何情况下，结果表明，遗传驱动的区域功能障碍可能会在功能障碍的大脑区域的结构中留下印记，例如在纹状体中。
Background: Mutations in the Parkin and PINK1 genes can cause parkinsonism. Since asymptomatic carriers of a single mutant allele of the Parkin or PINK1 gene display a presynaptic dopaminergic dysfunction in the striatum, they provide a unique in vivo model to study structural and functional reorganization in response to latent nigrostriatal dysfunction. We hypothesized that subclinical nigrostriatal neurodegeneration caused by these mutations would induce morphologic changes in the dysfunctional striatal gray matter.Methods: In asymptomatic carriers of a heterozygous Parkin (n = 13) or PINK1 (n = 10) mutation and 23 age-and sex-matched individuals without a mutation, we applied observer independent region-of-interest and voxel-based morphometry to high-resolution structural MRIs.Results: Relative to controls without a mutation, Parkin and PINK1 mutation carriers displayed a bilateral increase in gray matter volume in the putamen and the internal globus pallidus. In 8 of the 13 Parkin mutation carriers, the presynaptic dopaminergic function was studied with F-18-DOPA PET. The metabolic-morphometric regression analysis revealed that the linear decrease in individual presynaptic striatal F-18-DOPA uptake was linked to a reciprocal decrease in the striatal gray matter volume in the putamen bilaterally and in the left caudate nucleus.Conclusions: The alternative causes of the increased striatal gray matter volume may be either due to excessive levels of neuronal activity caused by chronic dopaminergic dysfunction or due to long-term adaptation to chronic nigrostriatal dysfunction actively compensating for the dopaminergic denervation. In any case, the results indicate that a genetically driven regional dysfunction may be imprinted in the structure of the dysfunctional brain region, for example in the striatum.