Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease.
Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease.
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纵向成像突出显示亨廷顿病中优先出现的基底神经节环路萎缩。
DOI：
10.1093/braincomms/fcad214
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发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
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作者：
亨廷顿病是由亨廷顿蛋白基因（HTT）中的CAG重复扩增引起的，该基因编码亨廷顿蛋白中的多聚谷氨酰胺，较长的CAG重复导致较早的发病年龄。变量“年龄”×（“CAG”-L），其中“年龄”是个体的当前年龄，“CAG”是重复长度，L是常数（反映阈值的近似值），称为“CAG年龄乘积”（CAP），能够同时考虑具有不同CAG重复扩增的许多个体，以分析任何变量并使用CAG年龄乘积分数作为X轴作图。结构MRI研究表明，进行性纹状体萎缩在可诊断的运动亨廷顿舞蹈病发作前多年就开始了，这一点得到了三大洲纵向多中心研究的证实，包括PREDICT-HD、TRACK-HD和IMAGE-HD。然而，以前的研究还没有阐明纹状体萎缩，其他基底神经节结构萎缩和其他脑区萎缩之间的关系。本研究使用单一图像分割算法并结合大量受试者的CAG年龄乘积评分数据，对所有三个纵向数据集进行了分析。此外，我们还使用了将局部萎缩正常化为全脑萎缩的策略，以确定哪些区域可能会发生优先变性。这使得详细描述与CAG年龄乘积评分相关的局部脑萎缩成为可能。基底神经节环路中的区域-尾状核、壳核、丘脑核、苍白球和黑质有明显的选择性萎缩。大脑的大多数其他区域似乎有缓慢但稳定的退化。这些结果支持（但肯定不能证明）亨廷顿病中基于回路的病理传播的假设，可能是由于突变型Htt蛋白的传播，尽管其他基于连接的机制是可能的。可能会建议与朊病毒样病变扩散或其他机制相关的治疗靶点。此外，它们对目前的神经外科治疗方法有影响，因为仅向尾状核和壳核递送治疗剂可能会错过早期受影响的其他结构，例如纹状体的中脑核和输出核、黑质和苍白球。Liu等人使用单一算法分析了三个大型纵向亨廷顿病成像数据集。他们发现参与基底神经节回路的区域发生了戏剧性的选择性萎缩。这些结果支持了亨廷顿病中病理学以电路为基础的传播的假设，并对当前的神经外科治疗方法有影响。
Huntington’s disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable ‘Age’ × (‘CAG’—L), where ‘Age’ is the current age of the individual, ‘CAG’ is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the ‘CAG Age Product’ (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington’s disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit—caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington’s disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus. Liu et al. analysed three large longitudinal Huntington’s disease imaging datasets using a single algorithm. They find dramatic selective atrophy of regions involved in the basal ganglia circuit. These results support the hypothesis of circuit-based spread of pathology in Huntington’s disease and have implications for current neurosurgical therapeutic approaches.
影响因子：
4.3
作者：
Tang X;Crocetti D;Kutten K;Ceritoglu C;Albert MS;Mori S;Mostofsky SH;Miller MI
通讯作者：
Miller MI
影响因子：
10.6
作者：
Aylward, Elizabeth H.;Liu, Dawei;Nopoulos, Peggy C.;Ross, Christopher A.;Pierson, Ronald K.;Mills, James A.;Long, Jeffrey D.;Paulsen, Jane S.
通讯作者：
Paulsen, Jane S.