背景:苯丙酮尿症(PKU)是一种罕见的先天性代谢错误,其特征是氨基酸苯丙氨酸(Phe)向酪氨酸的分解代谢受损。横断面研究表明,早期治疗PKU的成年人认知能力和神经激活略有改变。高Phe水平对成年期脑功能的影响,然而,仍然没有充分研究。因此,我们的目的是探讨4周口服Phe给药-模拟有控制的停用Phe限制并将Phe提高到非饮食状态-对工作记忆相关神经激活和脑血流量(CBF)的影响.
方法:我们进行了随机,安慰剂对照,双盲,交叉,非劣效性试验,以评估高Phe负荷对早期治疗的经典PKU成人中工作记忆相关神经激活和CBF的影响。纳入了27例早期治疗的经典PKU患者,并接受了工作记忆网络的功能磁共振成像(fMRI)和动脉自旋标记(ASL)MRI,以评估Phe和安慰剂干预四周前后的CBF。在四次研究访问中,功能磁共振成像工作记忆任务表现(反应时间和准确性)和血浆Phe,酪氨酸,并获得色氨酸水平。此外,通过1H-MR波谱测定脑Phe。
结果:Phe干预后血浆Phe和大脑Phe明显升高。然而,与安慰剂相比,Phe对神经激活和CBF没有显著影响.关于fMRI任务性能,观察到Phe干预对1-back反应时间的显着影响,在Phe干预后反应时间较慢,而与安慰剂干预相比,Phe干预后的3-back反应时间和准确性没有差异.
结论:本试验模拟停止Phe限制饮食4周的结果表明,高Phe负荷并没有以统计学显着方式均匀地影响神经标志物和认知。这些结果进一步促进了对成年期安全Phe水平的讨论,并表明停止Phe限制饮食四周并没有显示出脑功能的显着变化。
BACKGROUND: Phenylketonuria (PKU) is a rare inborn error of metabolism characterized by impaired catabolism of the amino acid phenylalanine (Phe) into tyrosine. Cross-sectional studies suggest slight alterations in cognitive performance and neural activation in adults with early-treated PKU. The influence of high Phe levels on brain function in adulthood, however, remains insufficiently studied. Therefore, we aimed to explore the effect of a four-week period of oral Phe administration - simulating a controlled discontinuation of Phe restriction and raising Phe to an off-diet scenario - on working memory-related neural activation and cerebral blood flow (CBF).
METHODS: We conducted a randomized, placebo-controlled, double-blind, crossover, non-inferiority trial to assess the effect of a high Phe load on working memory-related neural activation and CBF in early-treated adults with classical PKU. Twenty-seven patients with early-treated classical PKU were included and underwent functional magnetic resonance imaging (fMRI) of the working memory network and arterial spin labeling (ASL) MRI to assess CBF before and after a four-week intervention with Phe and placebo. At each of the four study visits, fMRI working memory task performance (reaction time and accuracy) and plasma Phe, tyrosine, and tryptophan levels were obtained. Additionally, cerebral Phe was determined by 1H-MR spectroscopy.
RESULTS: Plasma Phe and cerebral Phe were significantly increased after the Phe intervention. However, no significant effect of Phe compared to placebo was found on neural activation and CBF. Regarding fMRI task performance, a significant impact of the Phe intervention on 1-back reaction time was observed with slower reaction times following the Phe intervention, whereas 3-back reaction time and accuracy did not differ following the Phe intervention compared to the placebo intervention.
CONCLUSIONS: Results from this present trial simulating a four-week discontinuation of the Phe-restricted diet showed that a high Phe load did not uniformly affect neural markers and cognition in a statistically significant manner. These results further contribute to the discussion on safe Phe levels during adulthood and suggest that a four-week discontinuation of Phe-restricted diet does not demonstrate significant changes in brain function.