Brain White Matter Integrity Mediates the Relationship Between Phenylalanine Control and Executive Abilities in Children with Phenylketonuria
We tested the hypothesis that brain white matter integrity mediates the relationship between phenylalanine (Phe) control and executive abilities in children with phenylketonuria (PKU; N = 36). To do so, we examined mean diffusivity (MD) from diffusion tensor imaging (DTI) in two white matter brain regions (posterior parietal–occipital, PPO; centrum semiovale, CSO) and lifetime phenylalanine (Phe) exposure; the executive abilities examined included verbal strategic processing, nonverbal strategic processing, and working memory. Mediation modeling showed that MD in the PPO and CSO mediated the relationship between Phe exposure and nonverbal strategic processing, MD in the CSO mediated the relationship between Phe exposure and verbal strategic processing, and MD in the PPO mediated the relationship between Phe exposure and working memory. These exploratory findings demonstrate the importance of using sophisticated modeling procedures to understand the interplay among metabolic control, neural factors, and functional outcomes in individuals with PKU.
KeywordsBrain Executive abilities Mediation Neuroimaging Phenylketonuria White matter
The authors wish to thank those who participated in our research for their contributions. We also thank Suzin Blankenship and Laurie Sprietsma for their contributions to study management, as well as the physicians and staff of Washington University and Oregon Health & Science University who generously contributed to the study through recruitment and phenylalanine monitoring.
- Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Erlbaum, HillsdaleGoogle Scholar
- Das AM, Goedecke K, Meyer U, Kanzelmeyer N, Koch S, Illsinger S et al (2013) Dietary habits and metabolic control in adolescents and young adults with phenylketonuria: self-imposed protein restriction may be harmful. In: JIMD reports-case and research reports, vol 13. Springer, Heidelberg, pp 149–158Google Scholar
- Hood A, Antenor-Dorsey JAV, Rutlin J, Hershey T, Shimony JS, McKinstry RC et al (2014) Prolonged exposure to high and variable phenylalanine levels over the lifetime predicts brain white matter integrity in children with phenylketonuria. Mol Genet Metab 114(1):19–24Google Scholar
- Oishi K, Zilles K, Amunts K, Faria A, Jiang H, Li X et al (2008) Human brain white matter atlas: identification and assignment of common anatomical structures in superficial white matter. Neuroimage 43(3):447–457Google Scholar
- Scarabino T, Popolizio T, Tosetti M, Montanaro D, Giannatempo GM, Terlizzi R et al (2009) Phenylketonuria: white-matter changes assessed by 3.0-T magnetic resonance (MR) imaging, MR spectroscopy and MR diffusion. Radiol Med 114(3):461–474Google Scholar
- Shimony JS, McKinstry RC, Akbudak E, Aronovitz JA, Snyder AZ, Lori NF et al (1999) Quantitative diffusion-tensor anisotropy brain MR imaging: normative human data and anatomic analysis. Radiology 212(3):770–784Google Scholar
- Wechsler D (1999) Wechsler abbreviated scale of intelligence (WASI). The Psychological Corporation, San AntonioGoogle Scholar
- Weglage J, Fromm J, van Teeffelen-Heithoff A, Möller HE, Koletzko B, Marquardt T et al (2013) Neurocognitive functioning in adults with phenylketonuria: results of a long term study. Mol Genet Metab 110:S44–S48Google Scholar
- White DA, Connor LT, Nardos B, Shimony JS, Archer R, Snyder AZ et al (2010) Age-related decline in the microstructural integrity of white matter in children with early- and continuously-treated PKU: A DTI study of the corpus callosum. Mol Genet Metab 99:S41–S46Google Scholar
- White DA, Antenor-Dorsey JAV, Grange DK, Hershey T, Rutlin J, Shimony JS et al (2013) White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria. Mol Genet Metab 110(3):213–217Google Scholar