Brain glutathione in vascular mild cognitive impairment and cognitive correlates

Abstract Background Oxidative stress (OS) has been implicated in age‐related neurodegeneration and may be important in prodromal states such as vascular mild cognitive impairment (vMCI). Higher peripheral OS is reported in vMCI patients; however, the role of central antioxidant defenses in vMCI and their correlation to cognition is unclear. Glutathione (GSH) is a major brain antioxidant, and the current study assessed brain GSH in possible vMCI vs. controls. Methods Possible vMCI patients (1 standard deviation (SD) below population norms in verbal memory, executive function (EF), processing speed, or working memory, age 55‐85, and currently enrolled in a 6‐month exercise rehabilitation program due to having 2 or more vascular risk factors or previous vascular event) and cognitively‐normal (CN) controls were recruited. All participants received 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy) to quantify brain GSH at baseline in the anterior cingulate (AC) and occipital lobe (OL). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b). Results In 43 participants (mVCI n = 22, CN n = 21), AC‐GSH (I.U. ± SD) was higher in mVCI (1.96 ± 0.29) compared to CN (1.64 ± 0.48) (F (1,29.7) = 6.9, p = .01); this difference remained after correcting for cerebrospinal fluid (CSF) volume (F (1,28.4) = 6.5, p = .02), and controlling for age and sex (B [SE] = 0.33 [0.11], p = .007). There was no difference in OL‐GSH before or after correcting for CSF volume. Higher AC‐GSH, but not OL‐GSH, was correlated with poorer global cognition (Montreal Cognitive Assessment ‐Full score, B [SE] = 2.15, p = .03), and poorer EF performance (B [SE] = ‐0.67 [0.25], p < .001). These relationships remained significant after correcting for CSF volume. Conclusion The current study suggests an upregulation of AC glutathione in vMCI, which may reflect a compensatory increase in antioxidants as a response to oxidative stress challenges reported in these patients. Higher brain GSH in the AC region is correlated with poorer global cognition and executive function performance, suggesting a link between local brain antioxidant response and disease‐relevant cognitive domains.