Brain Age in Adult Patients With Early-Treated Phenylketonuria.

Adults with early-treated classical PKU showed a significantly elevated brain age gap (BAG) in the insula compared to healthy controls.

• The insula BAG was significantly higher in PKU patients than controls after correcting for multiple comparisons (puncor = 0.006, η2 = 0.07)
• This was the only brain age estimate to survive correction for multiple comparisons out of eight brain age estimates examined
• Study included 30 early-treated adults with classical PKU (age 19-48 years) and 59 age-, sex-, and education-comparable healthy controls
• 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

Patients with PKU showed differences in BAG for four out of eight brain age estimates examined.

• Eight brain age estimates were derived covering the full brain, cortical lobes, and subcortical regions
• Four of these estimates showed differences between PKU patients and controls
• Only the insular BAG survived correction for multiple comparisons
• The brain age gap (BAG) was defined as the difference between estimated brain age and chronological age

Cingulate BAG was positively associated with both concurrent and historical phenylalanine (Phe) levels.

• Associations between cingulate BAG and Phe levels had correlation coefficients of rs = 0.41–0.69 (puncor < 0.05)
• These correlations did not survive FDR-correction
• Both concurrent and historical Phe levels were associated with cingulate BAG
• Blood sampling was performed as part of the study protocol

Cingulate BAG was positively associated with white matter lesion load in PKU patients.

• The correlation between cingulate BAG and white matter lesion load was rs = 0.40 (puncor = 0.034)
• White matter lesion load was rated in patients using structural MRI
• This correlation did not survive FDR-correction
• White matter lesion load assessment was performed only in the PKU patient group

Subcortical and cingulate BAG were linked to cognitive performance in PKU patients.

• Correlations between subcortical and cingulate BAG and cognitive performance had coefficients of rs = -0.41 to 0.38 (puncor < 0.05)
• These correlations did not survive FDR-correction
• Cognitive assessment was conducted as part of the study protocol alongside mood assessment
• The direction of correlations (negative and positive) suggests both regions may relate to different aspects of cognition

The study population consisted of early-treated adults with classical PKU who underwent comprehensive multimodal assessment.

• Thirty early-treated adults with classical PKU aged 19–48 years were enrolled
• Fifty-nine healthy controls comparable in age, sex, and education were included
• All participants underwent structural MRI, cognitive and mood assessment, and blood sampling
• Machine learning models were trained to predict brain age from MRI-derived features across the full brain, cortical lobes, and subcortical regions