1454-P: Cerebral Glutathione Is Associated with Insulin Resistance in Older Individuals

Glutathione (GSH) is the primary defense against oxidative stress through its role in reducing reactive oxygen species (ROS) in the body, and its levels have been shown to be lower in both metabolic disease and aging. In this study, we sought to determine whether GSH levels in the human brain are lower in older individuals and whether these levels are associated with metabolic changes that come with age, such as increasing insulin resistance. 14 young (age 30.1 ±3.2 years, BMI 26.1 ±0.8 kg/m², A1c 5.3% ±0.1, HOMA-IR 1.6 mg(μU)/dL(mL) ±0.2) and 9 old (age 73.7 ±1.8, BMI 28.1 ±1.6, A1c 5.6 ±0.1, HOMA-IR 2.9 ±0.7) individuals underwent an oral glucose tolerance test as well as magnetic resonance spectroscopy (MRS) scanning at 4T for measurement of intracerebral GSH levels in the prefrontal cortex and striatum. Older individuals had higher levels of plasma ROS compared to younger individuals (P<0.001); however, there were no differences in plasma GSH levels (P=0.15). Intracerebral GSH levels (normalized to creatine(cr)) were not different between groups (P=0.76 prefrontal cortex, P=0.53 striatum). Amongst the older individuals, cerebral GSH/cr levels correlated inversely with HOMA-IR in both the striatum (r = -0.74, P=0.04) as well as prefrontal cortex (r= -0.95, P<0.001). Moreover, amongst older individuals, intracerebral GSH levels correlated inversely with performance on several measures of visual-spatial memory including the spatial working memory task (ρ= -0.9, P=0.003). There were no relationships between HOMA-IR and cerebral GSH levels amongst the younger individuals. Our findings indicate that amongst older individuals, increased insulin resistance is associated with diminished intracerebral GSH levels as well as visual-spatial cognitive deficits. These findings suggest that intracerebral GSH levels may be a useful marker for assessing the impact of metabolic dysfunction on neurocognitive function.