Changes in Physiological Concentrations of Blood Phenylalanine Produce Changes in Sensitive Parameters of Human Brain Function

Abstract

We previously demonstrated that increases of 1.0 mM in blood phenylalanine (Phe) decreased plasma L-DOPA, slowed brain electrical discharge, and prolonged performance on neuropsychological tests of higher integrative function. In this study, we evaluate the sensitivity of these tests of brain function during moderate elevation of plasma Phe. Six adult heterozygotes for phenylketonuria (PKU) and one homozygous normal volunteer were studied using a double-blind, double-crossover protocol of four 2-week intervals. Volunteers ingested a constant diet of 50 to 60 mg of Phe per kg per day supplemented by either 100 mg of Phe per kg per day or placebo. On the final two days of each study interval, the following parameters of brain function were evaluated: mean power frequency (MPF) of the EEG, plasma L-DOPA concentration, and cognitive function. The results indicate that plasma Phe rose in both heterozygotes and control during supplemental Phe ingestion from a mean of 99 ± 20 µM to 239 ± 166 µM. There was a wide range of interindividual variation with changes of plasma Phe between 7 µM and 403 µM, thus enabling evaluation of relative sensitivities among these parameters of brain function. Changes in EEG, L-DOPA, and cognitive function were all inversely related to plasma Phe changes between 330 and 403 µM. The MPF was the most sensitive of these parameters with changes seen with as low as 7 µM change in Phe. These changes were seen in the high-frequency α-band (8 to 12 cps) and gave a slope such that for every 100 µM change in plasma Phe, there was a 0.125-cps change in the inverse direction for brain wave function. This slope was similar to that seen in previous studies at changes in Phe concentration between 600 and 2400 µM. The plasma Phe concentrations used in these studies are attained by the chronic ingestion of 34 mg of aspartame per kg per day.