Liu Chin-Fu, Younes Laurent, Tong Xiao J, Hinkle Jared T, Wang Maggie, Phatak Sanika, Xu Xin, Bu Xuan, Looi Vivian, Bang Jee, Tabrizi Sarah J, Scahill Rachael I, Paulsen Jane S, Georgiou-Karistianis Nellie, Faria Andreia V, Miller Michael I, Ratnanather J Tilak, Ross Christopher A
Center for Imaging Science, Johns Hopkins University, Baltimore, MD 21218, USA.
Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
Brain Commun. 2023 Aug 18;5(5):fcad214. doi: 10.1093/braincomms/fcad214. eCollection 2023.
Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (), 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.
亨廷顿舞蹈症由亨廷顿基因（）中的CAG重复序列扩增引起，该基因编码亨廷顿蛋白中的多聚谷氨酰胺，CAG重复序列越长，发病年龄越早。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是一个常数（反映阈值的近似值），称为“CAG年龄乘积”（CAP），它使得能够同时考虑许多具有不同CAG重复序列扩增的个体，以便分析任何变量，并以CAG年龄乘积分数作为X轴进行绘图。结构磁共振成像研究表明，在可诊断的运动性亨廷顿舞蹈症发病前许多年，纹状体就开始进行性萎缩，这一点在包括PREDICT-HD、TRACK-HD和IMAGE-HD在内的三大洲纵向多中心研究中得到了证实。然而，先前的研究尚未阐明纹状体萎缩、其他基底神经节结构的萎缩以及其他脑区萎缩之间的关系。本研究使用单一图像分割算法对所有三个纵向数据集进行了综合分析，并结合了一系列CAG年龄乘积分数范围内大量受试者的数据。此外，我们采用了一种将区域萎缩归一化为全脑萎缩的策略，以确定哪些区域可能会发生优先退化。这使得能够详细描述与CAG年龄乘积分数相关的区域脑萎缩情况。参与基底神经节回路的区域——尾状核、壳核、伏隔核、苍白球和黑质——出现了显著的选择性萎缩。大脑的大多数其他区域似乎退化较慢但较为稳定。这些结果支持（但肯定不能证明）亨廷顿舞蹈症中基于回路的病理传播假说，这可能是由于突变的Htt蛋白传播所致，不过基于其他连接的机制也有可能。可能会提出与病理的朊病毒样传播或其他机制相关的治疗靶点。此外，它们对当前的神经外科治疗方法也有影响，因为仅将治疗药物输送到尾状核和壳核可能会遗漏早期受影响的其他结构，如伏隔核和纹状体的输出核、黑质和苍白球。
