Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington’s disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene-carriers much further from onset has yet to be explored. We characterised functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF Neurofilament Light, NfL) and measures of structural connectivity in asymptomatic gene-carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene-expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem HD and control brains showing enrichment of neuronal-specific genes that are differentially expressed in HD. Functional brain networks in asymptomatic preHD gene-carriers very far from disease onset, show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells.

中文翻译：

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年轻成人亨廷顿病的神经丝光相关连接与神经元基因有关

在临床诊断后 10-15 年的亨廷顿舞蹈病 (preHD) 的早期表现阶段，可以看到在存在结构退化的情况下功能网络连接的上调。然而，是否在基因携带者中看到广泛的网络连接变化在发病后更远的时间还有待探索。我们对整个大脑的功能网络连接进行了表征，并将其与疾病病理学负担（CSF Neurofilament Light，NfL）的测量和无症状基因携带者的结构连接测量相关联，平均发病后 24 年。我们将这些测量与皮质和皮质下基因表达的估计相关联。与对照组和 preHD 参与者相比，我们发现大脑任何地方的功能（或结构）连通性没有总体差异。然而，增加的功能连接，特别是在后皮质区域之间，与 preHD 参与者的 CSF NfL 水平增加相关。使用艾伦人脑图谱和表达加权细胞类型富集分析，我们证明这种功能连接上调发生在与神经元细胞特异性基因区域表达相关的皮质区域。使用来自死后 HD 和对照大脑的单核 RNAseq 数据验证了这种关系，显示了在 HD 中差异表达的神经元特异性基因的富集。远离疾病发作的无症状 preHD 基因携带者中的功能性大脑网络显示上调连接与疾病负担增加相关的证据。