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Regional Differences in Cerebral Phenylalanine Measured with Single Voxel Spectroscopy using PRESS localization and LCModel Quantification1Radiology, Brigham and Women's Hospital, Boston, MA, United States, 2Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States
Synopsis
This work describes a methodology for the quantification of phenylalanine in the brain, using standard single voxel spectroscopy with PRESS localization and LCModel quantification. The signals downfield from the water peak were modeled incorporating metabolite basis functions to the standard LCModel basis set. Phantom calibrations tailored for the acquisition protocol were performed to obtain corrected concentration ratios that showed significant regional differences (p<0.001) and high intrasubject correlation (R=0.73).
INTRODUCTION
Phenylketonurea (PKU)1,2 is a rare genetic condition where the absence of the enzyme phenylalanine hydroxylase, responsible for the conversion of phenylalanine (Phe) into tyrosine (Tyr), causes high Phe levels in blood and the accumulation of this amino acid in tissues. A high concentration of this metabolite in the brain leads to severe toxicity, hinders cognitive development, and if untreated, results in death. Although an early detection and screening of infants can be achieved with blood tests, monitoring of the disease, particularly in older children and adults who struggle with dietary compliance, has been limited.
Single voxel spectroscopy (SVS) allows for a direct measurement of Phe levels in brain tissue non-invasively. Methods for the quantification of Phe in the brain based on SVS have been proposed3,4,5. Nevertheless, due to its low concentration in the brain and the relatively low sensitivity of MRS, an accurate quantification remains a challenging task. Large volumes (up to 70mL) are typically necessary to improve SNR and sensitivity; however, it also eliminates the spatial context of the acquisition, which is of potential interest to study the accumulation of Phe in the brain of PKU patients.
This work describes a methodology for the detection and quantification of Phe in the brain using SVS with standard SNR-efficient PRESS localization and LCModel quantification7. This approach models the metabolite components upfield from the water signal and accounts for the relatively large chemical shift displacement (CSD) of Phe, which reduces the effective excitation volume for its major resonance frequencies.
METHODS
Signal Model: Basis functions for the metabolite components upfield from the water signal (Fig-1) were simulated using Vespa Simulation and Priorset software8. The relevant metabolites included phenylalanine (Phe), tyrosine (Tyr), homocarnosine (Hcar), and broad amide (NH) resonances at 7.8 ppm and 6.6 ppm from NAA (lNAA) and creatine (lCr).
In vivo Experiments: MR spectra of the posterior cingulate gyrus (PCG) and parietal white matter (PWM) of PKU subjects (N=17) and healthy controls (N=3) were measured at 3T (Trio; Siemens, Erlangen, Germany). PRESS localization was used with the following parameters: TE/TR=30/2000ms, 64 signal averages, and a voxel size of 30x30x30mm3 (27mL) and 40x20x30mm3 (24mL) for PCG and PWM, respectively.
Phantom Experiments: Phantom scans were performed to validate the fitting approach with high SNR. Four phantoms with varying NAA, Cr, Phe, and Tyr concentrations in the physiological concentration range were mixed and scanned using the same acquisition protocol (Fig‑2). Additionally, a correction factor for the signal loss related to the reduction of the effective volume due to the chemical shift displacement (CSD) of Phe was calculated to match the ground truth concentration ratios in the phantom.
Spectral Processing and Quantification: The MRS data was reconstructed using OpenMRSLab6 software and quantified with LCModel using a simulated basis set. The frequency range used for the fit was 0.2-4.0 ppm for the right fit and 6.4-7.6 ppm for the left fit. The measured Phe concentration was corrected for CSDE from the calibration. The effective volume size acquired for Phe resonance was 9mL for PCG and 8mL for PWM acquisition.
RESULTS AND DISCUSSION
The results of the phantom experiments used for the calibration and the in vivo spectral fit are presented in Fig-2 and Fig-3, respectively. Residuals in the left fit of in vivo data are comparable to the right fit, showing a relatively small contribution of baseline effects or macromolecules. The analysis of phenylalanine relative concentration (Phe/Cr) showed a significantly (p=0.00034) higher value in PWM than in PCG (Fig-4a) which suggests a higher accumulation in white matter tissue and the presence of regional differences in the distribution of Phe. Moreover, a significant correlation coefficient of R=0.728 with p=0.0047 was found in the Phe/Cr ratio between PWM and PCG brain regions (Fig-4b), which served as a validation for the quantification of relative concentrations.CONCLUSION
A methodology for the measurement of phenylalanine in the brain that uses standard well-established acquisition and quantification tools, and can be readily utilized in clinical studies, was described. The method was tested with a group of PKU subjects, showing consistency in the results. Furthermore, the obtained concentration ratios showed a significant correlation between different brain regions (PCG and PWM) with a significantly higher concentration in white matter tissue.Acknowledgements
No acknowledgement found.References
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