Haast Roy A M, De Coo Irenaeus F M, Ivanov Dimo, Khan Ali R, Jansen Jacobus F A, Smeets Hubert J M, Uludağ Kâmil
Centre for Functional and Metabolic Mapping, Robarts Research Institute, Western University, London, ON, Canada, N6A 5B7.
Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, the Netherlands.
Brain Commun. 2022 Feb 3;4(1):fcac024. doi: 10.1093/braincomms/fcac024. eCollection 2022.
Mutations of the mitochondrial DNA are an important cause of inherited diseases that can severely affect the tissue's homeostasis and integrity. The m.3243A > G mutation is the most commonly observed across mitochondrial disorders and is linked to multisystemic complications, including cognitive deficits. In line with experiments demonstrating the m.3243A > G's negative impact on neuronal energy production and integrity, m.3243A > G patients show cerebral grey matter tissue changes. However, its impact on the most neuron dense, and therefore energy-consuming brain structure-the cerebellum-remains elusive. In this work, we used high-resolution structural and functional data acquired using 7 T MRI to characterize the neurodegenerative and functional signatures of the cerebellar cortex in m.3243A > G patients. Our results reveal altered tissue integrity within distinct clusters across the cerebellar cortex, apparent by their significantly reduced volume and longitudinal relaxation rate compared with healthy controls, indicating macroscopic atrophy and microstructural pathology. Spatial characterization reveals that these changes occur especially in regions related to the frontoparietal brain network that is involved in information processing and selective attention. In addition, based on resting-state functional MRI data, these clusters exhibit reduced functional connectivity to frontal and parietal cortical regions, especially in patients characterized by (i) a severe disease phenotype and (ii) reduced information-processing speed and attention control. Combined with our previous work, these results provide insight into the neuropathological changes and a solid base to guide longitudinal studies aimed to track disease progression.
线粒体DNA突变是遗传性疾病的一个重要原因，可严重影响组织的稳态和完整性。m.3243A > G突变是线粒体疾病中最常见的突变，与多系统并发症有关，包括认知缺陷。与证明m.3243A > G对神经元能量产生和完整性有负面影响的实验一致，m.3243A > G患者显示出脑灰质组织变化。然而，其对神经元最密集、因此耗能最高的脑结构——小脑——的影响仍不清楚。在这项研究中，我们使用7 T MRI获得的高分辨率结构和功能数据来表征m.3243A > G患者小脑皮质的神经退行性和功能特征。我们的结果显示，与健康对照组相比，小脑皮质不同簇内的组织完整性发生改变，表现为体积和纵向弛豫率显著降低，表明存在宏观萎缩和微观结构病变。空间特征表明，这些变化尤其发生在与参与信息处理和选择性注意的额顶脑网络相关的区域。此外，基于静息态功能MRI数据，这些簇与额叶和顶叶皮质区域的功能连接减少，尤其是在具有以下特征的患者中：（i）严重疾病表型和（ii）信息处理速度和注意力控制降低。结合我们之前的工作，这些结果为神经病理变化提供了见解，并为指导旨在追踪疾病进展的纵向研究提供了坚实基础。
