Glutathione redox reaction: Target on early onset of neurodegenerative diseases in ASD

Autism spectrum disorder (ASD) is a neurodevelopmental condition that can present a wide range of support needs in adulthood associated with aging. It is currently unclear whether adults with ASD face an increased risk of developing neurodegenerative diseases (NDs) compared to the general population. While progression to dementia in older adults with autism is linked to cognitive decline, which is the leading cause of early-onset (before age 65) dementia related to oxidative stress (OS). Glutathione (GSH) is considered the brain's main antioxidant molecule, responsible for regulating OS during the aging process. Given the imminent risk of adults with ASD being diagnosed with early-onset neurodevelopmental disorder (ND), we studied the reduced GSH species in the anterior (ACC) and posterior (PCC) cingulate cortices as a target of sensory information (SI), using proton magnetic resonance spectroscopy (1H-MRS). GSH concentrations were assessed within a single 1H-MRS voxel in the ACC and PCC of all adult volunteers, separated into two study groups: ASD and typical development (TD). GSH concentrations in the ACC (3.08 mM; p = 0.05) were significantly lower in the ASD group compared to the TD group. Furthermore, the apparent potential energy (E0') of the GSSG/2GSH redox reaction was calculated using the Nernst equation, showing a significant difference between the means of the ACC vs. PCC groups. PCC of (-0.09190 mV; p = 0.0007) was observed in the ASD group, compared to the TD group (+0.01500 mV; p = 0.1638). These results demonstrate an imbalance in the GSH (reduction-oxidation) reaction present in the ASD group compared to the TD group. Our findings point to the development of potential treatments that directly target the mechanisms causing the imbalance in the GSH redox reaction in the brain, as a pathway toward next-generation, clinically active antioxidant therapies.