Quantification of protein synthesis in the human brain using L-[1-11C]-leucine PET: incorporation of factors for large neutral amino acids in plasma and for amino acids recycled from tissue

Abstract

The rate of incorporation of exogenous amino acids into brain proteins is indicative of the protein synthesis rate (PSR). The objective of this study was to assess the effect of plasma concentrations of leucine and large neutral amino acids (LNAAs) on the unidirectional uptake rate constant (Kcplx) of l-[1-(11)C]-leucine in the brain and to estimate the amino acid pool recycled from tissue.

Methods: Twenty-seven healthy adult volunteers (11 men and 16 women; age range, 20-50 y) underwent dynamic l-[1-(11)C]-leucine PET with arterial blood sampling. Data were analyzed with a standard 2-tissue-compartment model yielding the unidirectional uptake rate of plasma leucine into tissue (Kcplx = K(1)k(3)/(k(2) + k(3))) and the fraction of leucine originating from exogenous sources (lambda = k(2)/(k(2) + k(3))). PSR in brain was calculated as PSR = [Kcplx/lambda] x leucine.

Results: The mean plasma concentration of the sum of all LNAAs was 13% higher in men (981 +/- 86 micromol/L) than in women (850 +/- 76 micromol/L, P = 0.012), whereas the plasma leucine concentration was found to be similar in both sexes (men, 64 +/- 20 micromol/L; women, 58 +/- 21 micromol/L, P = 0.57). The whole-brain value for lambda was determined to be 0.64 +/- 0.03 and did not show a sex difference (P = 0.66). Whole-brain Kcplx values were significantly higher in women (0.0162 +/- 0.0024) than in men (0.0121 +/- 0.0031, P = 0.011); however, after normalization of the Kcplx to a standard plasma concentration of the sum of all LNAAs (Kcplx'), the Kcplx' was similar between the sexes (P = 0.21), as was the PSR' (1.24 +/- 0.49 micromol/L/min in men; 1.29 +/- 0.62 micromol/L/min in women, P = 0.87). No relationship between plasma leucine and Kcplx (r = -0.13, P = 0.63) was observed. Finally, there was a significant correlation between the PSR and the Kcplx derived using Patlak graphical analysis (rho = 0.65, P < 0.001).

Conclusion: We conclude that both the Kcplx macroparameter and the PSR are stable indices of brain protein synthesis and are appropriate measures for testing altered protein synthesis in neurologic disorders.