Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland.
Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland; Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern, Switzerland; Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine, Bern, Switzerland.
Neuroimage Clin. 2024;43:103654. doi: 10.1016/j.nicl.2024.103654. Epub 2024 Aug 14.
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).
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 H-MR spectroscopy.
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.
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.
苯丙酮尿症（PKU）是一种罕见的代谢性遗传疾病，其特征是氨基酸苯丙氨酸（Phe）的代谢受阻，无法转化为酪氨酸。横断面研究表明，早期治疗的 PKU 成年患者的认知表现和神经激活存在轻微改变。然而，高 Phe 水平对成年人大脑功能的影响研究不足。因此，我们旨在探讨为期四周的口服 Phe 给药 - 模拟控制停止 Phe 限制并将 Phe 提高至饮食外水平 - 对工作记忆相关神经激活和脑血流（CBF）的影响。
我们进行了一项随机、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 成年患者工作记忆相关神经激活和 CBF 的影响。共纳入 27 例早期治疗的经典 PKU 患者，在进行为期四周的 Phe 和安慰剂干预前后，进行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 CBF。在每个四项研究访视中，都获得了 fMRI 工作记忆任务表现（反应时间和准确性）和血浆 Phe、酪氨酸和色氨酸水平。此外，还通过 H-MR 光谱测定脑内 Phe。
Phe 干预后，血浆 Phe 和脑内 Phe 显著升高。然而，与安慰剂相比，Phe 干预对神经激活和 CBF 没有显著影响。关于 fMRI 任务表现，Phe 干预对 1 回反应时间有显著影响，Phe 干预后反应时间变慢，而 3 回反应时间和准确性在 Phe 干预后与安慰剂干预后没有差异。
本试验模拟了四周停止 Phe 限制饮食，结果表明高 Phe 负荷不会以统计学显著的方式均匀影响神经标志物和认知。这些结果进一步促进了关于成年期安全 Phe 水平的讨论，并表明停止 Phe 限制饮食四周不会导致大脑功能发生显著变化。
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