Phenylketonuria: brain phenylalanine concentrations relate inversely to cerebral protein synthesis

In phenylketonuria, elevated plasma phenylalanine concentrations may disturb blood-to-brain large neutral amino acid (LNAA) transport and cerebral protein synthesis (CPS). We investigated the associations between these processes, using data obtained by positron emission tomography with l-[1-¹¹C]-tyrosine (¹¹C-Tyr) as a tracer. Blood-to-brain transport of non-Phe LNAAs was modeled by the rate constant for ¹¹C-Tyr transport from arterial plasma to brain tissue (K₁), while CPS was modeled by the rate constant for ¹¹C-Tyr incorporation into cerebral protein (k₃). Brain phenylalanine concentrations were measured by magnetic resonance spectroscopy in three volumes of interest (VOIs): supraventricular brain tissue (VOI 1), ventricular brain tissue (VOI 2), and fluid-containing ventricular voxels (VOI 3). The associations between k₃ and each predictor variable were analyzed by multiple linear regression. The rate constant k₃ was inversely associated with brain phenylalanine concentrations in VOIs 2 and 3 (adjusted R²=0.826, F=19.936, P=0.021). Since brain phenylalanine concentrations in these VOIs highly correlated with each other, the specific associations of each predictor with k₃ could not be determined. The associations between k₃ and plasma phenylalanine concentration, K₁, and brain phenylalanine concentrations in VOI 1 were nonsignificant. In conclusion, our study shows an inverse association between k₃ and increased brain phenylalanine concentrations.