Reliability and regional specificity of glutathione and gamma-aminobutyric acid edited magnetic resonance spectroscopy in the human subcortex

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PROJECT SUMMARY A biological test to diagnose, track, and predict Parkinson’s disease (PD) remains elusive. Development of such a test will aid the detection, treatment, and possible prevention of PD. Novel applications of neuroimaging technologies for anatomically localized measurements of specific brain chemicals show promise in meeting this need. Our proposed work will adapt a recently developed magnetic resonance imaging technique to measure chemicals in deep brain structures in vivo. This work aims to evaluate the reliability and regional specificity of this technique in healthy adult humans and will selectively measure chemicals in target brain areas implicated in PD. Establishing measurement reliability and anatomical specificity is an important prerequisite for the future use of the protocol in clinical research and will lay the foundation for studies aimed at developing this approach as a neuroimaging biomarker of PD to aid in clinical diagnosis, disease tracking, and evaluation of treatment efficacy. The loss of dopamine in the basal ganglia is a defining feature of PD. However, abnormal levels of other brain chemicals may precede the loss of dopamine and accelerate PD progression. These chemicals include glutathione (GSH) and gamma-aminobutyric acid (GABA). GSH is a naturally occurring antioxidant that protects brain cells from oxidative stress which results from chemical reactions with unstable oxygen-containing molecules. GSH neutralizes these unstable molecules. Insufficient levels of GSH hasten dopamine cell loss in animal models of PD and are also observed in post-mortem deep brain tissue from individuals with PD. GABA is another naturally occurring chemical and is the principle inhibitory neurotransmitter in the adult human brain. GABA levels in deep brain structures of individuals with PD correlate with motor symptom severity. In vivo measurement of GSH and GABA in targeted deep brain regions could have far reaching impacts by helping to predict whether a person will develop PD, track disease progression, and assess treatment efficacy. Single-voxel magnetic resonance spectroscopy (MRS) is a non-invasive imaging method for quantifying the amounts of specific molecules within targeted anatomical regions of interest. A specialized MRS sequence was recently developed for the simultaneous measurement of GSH and GABA in the human brain, but has not been used to study deep brain areas commonly affected in PD. The proposed work will apply this MRS scan in the substantia nigra and thalamus, two regions that exhibit abnormal GSH and GABA levels in PD. Thirty healthy adults will undergo MRS scanning twice, on separate days. At each session, simultaneous measurements of GSH and GABA will be taken in three regions of interest: 1) the substantia nigra on both sides of the brain, 2) the left thalamus, and 3) the right thalamus. Each scanning session will take approximately 60 minutes. Comparisons across days will evaluate reliability and comparisons between regions will assess regional specificity. The data will provide benchmarks for future translation of the method to PD clinical trials. Immediate next steps for this work will focus on the development of the imaging protocol as a diagnostic and preclinical tool.