Department of Psychological & Brain Sciences, Campus Box 1125, Washington University, St. Louis, MO, United States.
Department of Psychological & Brain Sciences, Campus Box 1125, Washington University, St. Louis, MO, United States; Department of Biomedical Engineering, Washington University, St. Louis, MO, United States.
Neuroimage Clin. 2019;23:101916. doi: 10.1016/j.nicl.2019.101916. Epub 2019 Jul 2.
Phenylketonuria (PKU) is a recessive disorder characterized by disruption in the metabolism of the amino acid phenylalanine (Phe). Prior research indicates that individuals with PKU have substantial white matter (WM) compromise. Much less is known about gray matter (GM) in PKU, but a small body of research suggests volumetric differences compared to controls. To date, developmental trajectories of GM structure in individuals with PKU have not been examined, nor have trajectories of WM and GM been examined within a single study. To address this gap in the literature, we compared longitudinal brain development over a three-year period in individuals with PKU (n = 35; 18 male) and typically-developing controls (n = 71; 35 male) aged 7-21 years. Using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI), we observed whole-brain and regional WM differences between individuals with PKU and controls, which were often exacerbated with increasing age. In marked contrast with trajectories of WM development, trajectories of GM development did not differ between individuals with PKU and controls, indicating that neuropathology in PKU is more prominent in WM than GM. Within individuals with PKU, mediation analyses revealed that whole-brain mean diffusivity (MD) and regional MD in the corpus callosum and centrum semiovale mediated the relationship between dietary treatment compliance (i.e., Phe control) and executive abilities, suggesting a plausible neurobiological mechanism by which Phe control may influence cognitive outcomes. Our findings clarify the specificity, timing, and cognitive consequences of whole-brain and regional WM pathology, with implications for treatment and research in PKU.
苯丙酮尿症（PKU）是一种常染色体隐性遗传病，其特征是氨基酸苯丙氨酸（Phe）代谢紊乱。先前的研究表明，PKU 患者的大脑白质（WM）有明显的损伤。但关于 PKU 患者大脑灰质（GM）的研究相对较少，但有一些研究表明与对照组相比存在体积差异。迄今为止，尚未对 PKU 患者 GM 结构的发育轨迹进行研究，也没有在单一研究中研究 WM 和 GM 的轨迹。为了解决这一文献空白，我们比较了 35 名 PKU 患者（18 名男性）和 71 名正常发育对照者（35 名男性）在 7-21 岁期间的三年大脑纵向发育情况。使用弥散张量成像（DTI）和结构磁共振成像（MRI），我们观察到 PKU 患者和对照组之间存在全脑和区域 WM 差异，这些差异随着年龄的增长而加剧。与 WM 发育轨迹形成鲜明对比的是，PKU 患者和对照组之间的 GM 发育轨迹没有差异，这表明 PKU 中的神经病理学在 WM 中比 GM 更为突出。在 PKU 患者中，中介分析表明，全脑平均弥散度（MD）和胼胝体及半卵圆中心的区域 MD 介导了饮食治疗依从性（即 Phe 控制）与执行能力之间的关系，这表明 Phe 控制可能通过某种神经生物学机制影响认知结果。我们的研究结果阐明了全脑和区域 WM 病理学的特异性、时间进程和认知后果，对 PKU 的治疗和研究具有重要意义。
