最常见的线粒体DNA(mtDNA)突变之一,碱基对3243的A到G的转变与大脑的变化有关,除了常见的听力问题,糖尿病和肌病。然而,到目前为止,尚未提供m.3243A>G患者大脑的详细定量描述。在这项研究中,7T的超高场MRI以及基于体积和表面的数据分析方法用于突出形态(即萎缩)-,患者(N=22)和健康对照(N=15)之间的微观结构(即髓鞘和铁浓度)和代谢(即脑血流量)相关差异。在7T时使用定量MRI使我们能够以高精度和灵敏度检测大脑中生物物理过程的细微变化,除了通常评估的病变和萎缩。此外,在患者人群中评估了血液和尿液上皮细胞中m.3243A>G突变负荷对这些MRI测量的影响,并揭示了血液水平最能指示大脑状态和疾病严重程度,基于MRI和神经心理学数据。形态MRI数据显示皮质广泛减少,皮质下和小脑灰质体积,除了明显扩大的心室。此外,基于表面的分析揭示了皮层厚度(例如听觉皮层)的大脑区域特异性变化,在T1,T2*和脑血流量中,作为突变负荷的函数,这通常与m.3243A>G相关的临床症状(例如听力障碍)有关。此外,与注意力控制相关的几个区域(例如额叶中回),感觉运动网络(例如中央沟库)和默认模式网络(例如前突)的特征在于皮质厚度的变化,T1、T2*和/或脑血流量,这在以前的MRI研究中没有描述。最后,几个假设,基于血管,m.3243A>G突变的代谢或星形胶质影响,讨论了可能解释潜在病理生物学的原因。最后,这是首个7T,也是针对该患者人群的最大MRI研究,该研究提供了m.3243A>G突变的宏观脑相关性,提示线粒体疾病的潜在MRI生物标志物,并可能指导未来(纵向)研究广泛追踪神经病理学和临床变化.
One of the most common mitochondrial DNA (mtDNA) mutations, the A to G transition at base pair 3243, has been linked to changes in the brain, in addition to commonly observed hearing problems, diabetes and myopathy. However, a detailed quantitative description of m.3243A>G patients\' brains has not been provided so far. In this
study, ultra-high field MRI at 7T and volume- and surface-based data analyses approaches were used to highlight morphology (i.e. atrophy)-, microstructure (i.e. myelin and iron concentration)- and metabolism (i.e. cerebral blood flow)-related differences between patients (N = 22) and healthy controls (N = 15). The use of quantitative MRI at 7T allowed us to detect subtle changes of biophysical processes in the brain with high accuracy and sensitivity, in addition to typically assessed lesions and atrophy. Furthermore, the effect of m.3243A>G mutation load in blood and urine epithelial cells on these MRI measures was assessed within the patient population and revealed that blood levels were most indicative of the brain\'s state and disease severity, based on MRI as well as on neuropsychological data. Morphometry MRI data showed a wide-spread reduction of cortical, subcortical and cerebellar gray matter volume, in addition to significantly enlarged ventricles. Moreover, surface-based analyses revealed brain area-specific changes in cortical thickness (e.g. of the auditory cortex), and in T1, T2* and cerebral blood flow as a function of mutation load, which can be linked to typically m.3243A>G-related clinical symptoms (e.g. hearing impairment). In addition, several regions linked to attentional control (e.g. middle frontal gyrus), the sensorimotor network (e.g. banks of central sulcus) and the default mode network (e.g. precuneus) were characterized by alterations in cortical thickness, T1, T2* and/or cerebral blood flow, which has not been described in previous MRI studies. Finally, several hypotheses, based either on vascular, metabolic or astroglial implications of the m.3243A>G mutation, are discussed that potentially explain the underlying pathobiology. To conclude, this is the first 7T and also the largest MRI
study on this patient population that provides macroscopic brain correlates of the m.3243A>G mutation indicating potential MRI biomarkers of mitochondrial diseases and might guide future (longitudinal) studies to extensively track neuropathological and clinical changes.