Phenylketonuria is a rare metabolic disease resulting from a deficiency of the enzyme phenylalanine hydroxylase. Recent cross-sectional evidence suggests that early-treated adults with phenylketonuria exhibit alterations in cortical grey matter compared to healthy peers. However, the effects of high phenylalanine exposure on brain structure in adulthood need to be further elucidated. In this double-blind, randomised, placebo-controlled crossover trial, we investigated the impact of a four-week high phenylalanine exposure on the brain structure and its relationship to cognitive performance and metabolic parameters in early-treated adults with phenylketonuria. Twenty-eight adult patients with early-treated classical phenylketonuria (19-48 years) underwent magnetic resonance imaging before and after the four-week phenylalanine and placebo interventions (four timepoints). Structural T1-weighted images were preprocessed and evaluated using DL+DiReCT, a deep-learning-based tool for brain morphometric analysis. Cortical thickness, white matter volume, and ventricular volume were compared between the phenylalanine and placebo periods. Brain phenylalanine levels were measured using 1H spectroscopy. Blood levels of phenylalanine, tyrosine, and tryptophan were assessed at each of the four timepoints, along with performance in executive functions and attention. Blood phenylalanine levels were significantly higher after the phenylalanine period (1441µmol/L) than after the placebo period (873µmol/L, P<0.001). Morphometric analyses revealed a statistically significant decrease in cortical thickness in 17 out of 60 brain regions after the phenylalanine period compared to placebo. The largest decreases were observed in the right pars orbitalis (point estimate=-0.095mm, P<0.001) and the left lingual gyrus (point estimate=-0.070mm, P<0.001). Bilateral white matter and ventricular volumes were significantly increased after the phenylalanine period. However, the structural alterations in the Phe-placebo group returned to baseline measures following the washout and placebo period. Additionally, elevated blood and brain phenylalanine levels were related to increased bilateral white matter volume (rs=0.43 to 0.51, P≤0.036) and decreased cortical thickness (rs=-0.62 to -0.39, not surviving FDR correction) after the phenylalanine and placebo periods. Moreover, decreased cortical thickness was correlated with worse cognitive performance after both periods (rs=-0.54 to -0.40, not surviving FDR correction). These findings provide evidence that a four-week high phenylalanine exposure in adults with phenylketonuria results in transient reductions of the cortical grey matter and increases in white matter volume. Further research is needed to determine the potential long-term impact of high phenylalanine levels on brain structure and function in adults with phenylketonuria.

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苯丙酮尿症成人高苯丙氨酸暴露后短暂的大脑结构变化

苯丙酮尿症是一种罕见的代谢性疾病，由苯丙氨酸羟化酶缺乏引起。最近的横断面证据表明，与健康同龄人相比，接受早期治疗的苯丙酮尿​​症成年人的皮质灰质发生了变化。然而，高苯丙氨酸暴露对成年期大脑结构的影响需要进一步阐明。在这项双盲、随机、安慰剂对照的交叉试验中，我们研究了为期 4 周的高苯丙氨酸暴露对早期治疗的苯丙酮尿​​症成人大脑结构的影响及其与认知表现和代谢参数的关系。 28 名早期治疗的经典苯丙酮尿症成年患者（19-48 岁）在为期 4 周的苯丙氨酸和安慰剂干预（四个时间点）之前和之后接受了磁共振成像。使用 DL+DiReCT（一种基于深度学习的大脑形态测量分析工具）对结构 T1 加权图像进行预处理和评估。比较苯丙氨酸组和安慰剂组的皮质厚度、白质体积和心室体积。使用 1H 光谱测量脑苯丙氨酸水平。在四个时间点的每个时间点评估血液中苯丙氨酸、酪氨酸和色氨酸的水平，以及执行功能和注意力的表现。苯丙氨酸期后的血液苯丙氨酸水平（1441μmol/L）显着高于安慰剂期后（873μmol/L，P＜0.001）。形态测量分析显示，与安慰剂相比，苯丙氨酸期后 60 个大脑区域中有 17 个区域的皮质厚度出现统计学显着下降。最大的下降出现在右侧眼眶部（点估计=-0.095mm，P<0.001）和左侧舌回（点估计=-0.070mm，P<0.001）。苯丙氨酸期后双侧白质和心室体积显着增加。然而，Phe-安慰剂组的结构变化在清洗期和安慰剂期后恢复到基线测量值。此外，苯丙氨酸和安慰剂治疗后，血液和脑中苯丙氨酸水平升高与双侧白质体积增加（rs=0.43至0.51，P≤0.036）和皮质厚度减少（rs=-0.62至-0.39，不经FDR校正）相关。期间。此外，皮质厚度的减少与这两个时期后较差的认知表现相关（rs=-0.54 至 -0.40，不存在 FDR 校正）。这些发现提供的证据表明，患有苯丙酮尿症的成人连续四周接触高苯丙氨酸会导致皮质灰质短暂减少和白质体积增加。需要进一步的研究来确定高苯丙氨酸水平对苯丙酮尿症成人大脑结构和功能的潜在长期影响。