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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

Senthil K. Sundaram1,2, Otto Muzik1–3,, Diane C. Chugani1,3, Fanrong Mu3, Thomas J. Mangner3 and Harry T. Chugani1–3,

1 Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University School of Medicine, Detroit, Michigan; 2 Department of Neurology, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University School of Medicine, Detroit, Michigan; and 3 Department of Radiology, Children's Hospital of Michigan, Detroit Medical Center, Wayne State University School of Medicine, Detroit, Michigan


Figure 1
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  		FIGURE 1.  (A) Time course of 11C concentration associated with total plasma, unmetabolized L-[1-11C]-leucine, and L-[1-11C]-leucine in plasma protein. (B) Fraction of unmetabolized free L-[1-11C]-leucine relative to total 11C concentration in plasma fitted with a 3-parameter (offset, {alpha}, ß) sigmoidal function. Parameter values that best fit data are reported. Fitted curve explains more than 90% of variance in data.

 

Figure 2
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  		FIGURE 2.  (Top) Simplified 2-tissue-compartment model for labeled leucine, with k2 representing effective loss of 11C tracer from tissue and k3 representing effective incorporation of L-[1-11C]-leucine into protein. Tracer concentration in combined free and metabolic compartment is denoted as Cf+m, and tracer concentration in protein pool is denoted as Cb. (Bottom) Simplified 2-tissue-compartment model for unlabeled leucine, with krec representing recycled leucine as product of brain protein breakdown. Models describing L-[1-11C]-leucine and unlabeled leucine differ only with respect to krec, which is zero for L-[1-11C]-leucine.

 

Figure 3
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  		FIGURE 3.  (Top) Averaged images representing Kcplx macroparameter from 20 to 60 after injection at 3 levels through brain. (Bottom) Corresponding parametric images obtained from representative subject. Kcplx values derived from parametric images agreed within 3% with those derived from compartmental analysis of time–activity curves.

 

Figure 4
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  		FIGURE 4.  Box plot showing inverse relationship between plasma concentration of sum of all LNAAs (A) and Kcplx macroparameter (B). Box itself contains middle 50% of data, with line in box indicating median value. Ends of vertical lines, representing maximum and minimum data values, and points outside this range are considered outliers. The significantly lower total LNAA levels found in women (P = 0.012) appear related to significantly higher estimates of Kcplx macroparameter in women than in men (P = 0.011). (C) Kcplx macroparameter value for men and women after normalization to standard total plasma LNAA concentration of 1,000 µmol/L.

 

Figure 5
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  		FIGURE 5.  Inverse relationship between estimated Kcplx macroparameter (mL/g/min) and measured plasma total LNAA concentration (µmol/L). Correlation analysis suggests statistical trend between these 2 variables.

 

Figure 6
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  		FIGURE 6.  Box-plot comparison of whole-brain PSR values obtained for men and women. Middle 50% of data lie within box, with ends of vertical lines representing maximum and minimum data values. Points outside minimum and maximum values are considered outliers. (A) PSR values calculated on basis of leucine kinetics without correction for plasma total sum of LNAAs. (B) PSR values after normalization of plasma total sum of LNAAs to standard value of 1,000 µmol/L (PSR'). Although neither measure of PSR is significantly different between the sexes, correction for plasma total sum of all LNAAs results in smaller difference between mean male and female PSRs, indicating a small effect of total plasma LNAA levels on PSR measure.

 

Figure 7
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  		FIGURE 7.  (A) Patlak plot obtained from representative subject showing linear behavior of transformed curves at times later than 30 min after injection. Slope of fitted lines represents Kcplx estimates, which closely correspond to Kcplx values derived using compartmental model. (B) Relationship between regional PSR values and Kcplx macroparameter determined using Patlak graphical analysis. Brain regions include visual cortex, brain stem, cerebellar thalamus, frontal cortex, and white matter. Line of identity is displayed as dotted line. Plot shows excellent correlation between these 2 measures of PSR ({rho} = 0.65).

 




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