Reversible white matter changes following a 4-week high phenylalanine exposure in adults with phenylketonuria

Abstract

Alterations in brain structure are frequently observed in adults with early-treated phenylketonuria (PKU) compared to healthy controls, with cerebral white matter (WM) being particularly affected. The extent to which temporary elevation of phenylalanine (Phe) levels impacts WM remains unclear. We conducted a double-blind, randomised, placebo-controlled crossover trial to investigate the effects of a 4-week high Phe exposure on cerebral WM and its relationship to cognitive performance and metabolic parameters in adults with PKU. In this study, 27 adults with early-treated classical PKU (aged 19-48 years) underwent diffusion tensor imaging (DTI) before and after the 4-week Phe and placebo interventions. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were analysed using tract-based spatial statistics. Neuropsychological examinations at each timepoint evaluated executive functions and attention. Additionally, brain Phe levels were measured using MR spectroscopy, and blood levels of Phe, tyrosine, and tryptophan were assessed after an overnight fast. Following the Phe period, significant decreases in AD, MD, and RD were observed compared to the placebo period, particularly in the posterior corona radiata and optic radiation. Notably, these WM changes were reversible in patients who first received Phe (n = 13). Cognitive performance and metabolic parameters were not significantly related to DTI scalars after the Phe period. In conlcusion, a 4-week Phe elevation induced reversible microstructural alterations in cerebral WM. Further investigation is necessary to determine the clinical implication of these changes.

Keywords: PKU; cerebral white matter; cognition; phenylalanine intervention; randomised placebo‐controlled trial; reversibility.

FIGURE 1

Voxel‐wise difference in WM microstructure between Phe and placebo periods indicated by t‐values, with larger values reflecting stronger changes in Diffusion Tensor Imaging (DTI) scalars. Regions with significantly decreased DTI scalars after the Phe period are marked by the colour continuum (the lighter (yellower), the stronger the decrease). Blue regions represent the mean fractional anisotropy (FA) skeleton. Voxel‐wise differences are displayed for mean diffusivity (MD, upper row), axial diffusivity (AD, middle row), and radial diffusivity (RD, bottom row). Fractional anisotropy did not show any significant differences between Phe and placebo periods after correction for multiple comparisons and is therefore not shown here.