Brain Age in Adult Patients With Early‐Treated Phenylketonuria

Structural brain alterations have been observed in individuals with phenylketonuria (PKU); however, the potential impact of PKU on brain aging remains unexplored. This study investigated brain age in adults with early-treated classical PKU compared to healthy controls. Thirty early-treated adults with classical PKU (age 19-48 years) and 59 age-, sex-, and education-comparable healthy controls underwent structural magnetic resonance imaging (MRI), cognitive and mood assessment, and blood sampling. Brain age was estimated using machine learning models trained to predict brain age from MRI-derived features across the full brain, cortical lobes, or subcortical regions. The brain age gap (BAG)-the difference between brain age and chronological age-was calculated. In addition, white matter lesion load was rated in patients. While patients with PKU showed differences in BAG for four out of eight brain age estimates, only the BAG in the insula was significantly higher in PKU than controls after correcting for multiple comparisons (p_uncor = 0.006, η² = 0.07). The cingulate BAG was positively associated with concurrent and historical Phe levels (r_s = 0.41-0.69, p_uncor < 0.05) and with white matter lesion load (r_s = 0.40, p_uncor = 0.034). Further, subcortical and cingulate BAG were linked to cognitive performance (r_s = -0.41-0.38, p_uncor < 0.05). These correlations did not survive FDR-correction. In conclusion, the elevated insular BAG in adults with early-treated PKU may reflect atypical brain development due to cumulative effects of early-life or lifelong metabolic disturbances. Longitudinal studies are warranted to elucidate brain aging trajectories and their cognitive implications in PKU.