Computational Neuroimaging Group (CNG), School of Medicine, Trinity College Dublin, Dublin, D02 RS90, Ireland.
Department of Neurology, St James's Hospital, Dublin, Ireland.
J Neurol. 2023 Sep;270(9):4235-4247. doi: 10.1007/s00415-023-11764-5. Epub 2023 May 13.
The characterisation of presymptomatic disease-burden patterns in asymptomatic mutation carriers has a dual academic and clinical relevance. The understanding of disease propagation mechanisms is of considerable conceptual interests, and defining the optimal time of pharmacological intervention is essential for improved clinical trial outcomes.
In a prospective, multimodal neuroimaging study, 22 asymptomatic C9orf72 GGGGCC hexanucleotide repeat carriers, 13 asymptomatic subjects with SOD1, and 54 "gene-negative" ALS kindreds were enrolled. Cortical and subcortical grey matter alterations were systematically appraised using volumetric, morphometric, vertex, and cortical thickness analyses. Using a Bayesian approach, the thalamus and amygdala were further parcellated into specific nuclei and the hippocampus was segmented into anatomically defined subfields.
Asymptomatic GGGGCC hexanucleotide repeat carriers in C9orf72 exhibited early subcortical changes with the preferential involvement of the pulvinar and mediodorsal regions of the thalamus, as well as the lateral aspect of the hippocampus. Volumetric approaches, morphometric methods, and vertex analyses were anatomically consistent in capturing focal subcortical changes in asymptomatic C9orf72 hexanucleotide repeat expansion carriers. SOD1 mutation carriers did not exhibit significant subcortical grey matter alterations. In our study, none of the two asymptomatic cohorts exhibited cortical grey matter alterations on either cortical thickness or morphometric analyses.
The presymptomatic radiological signature of C9orf72 is associated with selective thalamic and focal hippocampal degeneration which may be readily detectable before cortical grey matter changes ensue. Our findings confirm selective subcortical grey matter involvement early in the course of C9orf72-associated neurodegeneration.
无症状突变携带者的无症状疾病负担模式的特征具有双重学术和临床意义。了解疾病传播机制具有重要的概念意义，而确定药物干预的最佳时间对于改善临床试验结果至关重要。
在一项前瞻性的多模态神经影像学研究中，纳入了 22 名无症状 C9orf72 GGGGCC 六核苷酸重复携带者、13 名无症状 SOD1 患者和 54 名“基因阴性”ALS 家族。使用体积、形态、顶点和皮质厚度分析系统评估皮质和皮质下灰质改变。使用贝叶斯方法，进一步将丘脑和杏仁核分割成特定核，并将海马体分割成解剖定义的亚区。
无症状 C9orf72 中的 GGGGCC 六核苷酸重复携带者表现出早期的皮质下变化，丘脑的苍白球和中背侧区域以及海马体的外侧区域优先受累。体积方法、形态方法和顶点分析在捕获无症状 C9orf72 六核苷酸重复扩展携带者的局灶性皮质下变化方面具有解剖一致性。SOD1 突变携带者没有表现出明显的皮质下灰质改变。在我们的研究中，两个无症状队列都没有在皮质厚度或形态分析上表现出皮质灰质改变。
C9orf72 的无症状放射学特征与选择性丘脑和局灶性海马体变性相关，这可能在皮质灰质变化之前就很容易检测到。我们的研究结果证实了 C9orf72 相关神经退行性变早期选择性皮质下灰质受累。
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