Assessment of brain metabolite correlates of AAV-mediated overexpression of human alpha-synuclein in cortical neurons by in vivo(1) H-MR spectroscopy at 9.4 T

In this study, we used proton-localized spectroscopy ((1) H-MRS) for the acquisition of the neurochemical profile longitudinally in a novel rat model of human wild type alpha-synuclein (a-syn) overexpression. Our goal was to find out if the increased a-syn load in this model could be linked to changes in metabolites in the frontal cortex. Animals injected with AAV vectors encoding for human a-syn formed the experimental group, whereas green fluorescent protein (GFP) expressing animals were used as the vector-treated control group and a third group of uninjected animals were used as naïve controls. Data was acquired at 2, 4 and 8 month time-points. Nineteen metabolites were quantified in the MR spectra using LCModel software. Based on 92 spectra, we evaluated any potential gender effect and found that Lactate levels were lower in males compared to females, while the opposite was observed for Ascorbate. Next, we assessed the effect of age and found increased levels of GABA, Tau and GPC+PCho. Finally, we analyzed the effect of treatment and found that Lactate levels (p=0.005) were specifically lower in the a-syn group compared to the GFP and control groups. Additionally, Ascorbate levels (p=0.05) were increased in the vector-injected groups, while glucose levels remained unchanged. This study indicates that the metabolic switch between Glucose-Lactate could be detectable in-vivo and might be modulated by Ascorbate. No concomitant changes were found in markers of neuronal integrity (e.g. NAA) consistent with the fact that a-syn overexpression in cortical neurons did not result in neurodegeneration in this model. This article is protected by copyright. All rights reserved.