Oxidative stress mediates the effect of apathy on executive function in those at risk of vascular cognitive impairment

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AbstractBackgroundPeople with coronary artery disease (CAD) are at a high risk of developing mild vascular cognitive impairment and those with cognitive decline have been shown to have higher ratios of late to early lipid peroxidation markers indicating oxidative stress. Neuropsychiatric symptoms can precede biomarker abnormalities e.g., depressive symptoms. Apathy has previously been linked to cognitive impairment, particularly executive dysfunction, but the physiological pathways underlying this relationship have not been investigated. This study investigated whether oxidative stress mediates a relationship between apathy and executive function in CAD.MethodParticipants with CAD were identified from a Cardiac Rehabilitation Program at the time of intake. The Apathy Evaluation Scale (AES) was used to measure apathy and executive function (EF) was measured via FAS test for phonemic fluency, animal naming test for semantic fluency and trails making test B. Markers of late (8‐isoprostane, 8‐ISO) and early (lipid hydroperoxides, LPH) lipid peroxidation/oxidative stress were measured in the serum. Mediation effects were tested using the PROCESS macro (version 3.4) for SPSS. A bias corrected inferential bootstrapping method with 10,000 permutations was used to obtain a 95% confidence interval (CI) for the indirect effect.ResultAmong patients with CAD (n=214, 20% women, mean±SD age= 63.2±7.5 years, years of education [YOE]= 15.8±3.4, AES score= 28.2±8.7, composite z score for EF= ‐0.18±0.71), the ratio of 8‐ISO to LPH mediated the relationship between apathy and EF in a model controlling for age, sex and YOE. The standardized regression coefficients between apathy and ratio of 8‐ISO to LPH (0.4961, p=0.02) and that between the ratio of 8‐ISO to LPH and EF (‐0.0053, p=0.005) were both statistically significant. Bootstrapping produced a statistically significant unstandardized indirect effect (‐0.0027 95% CI: ‐0.0087, ‐0.0007).ConclusionThe results suggest that oxidative stress, specifically late markers of lipid peroxidation, plays a role in facilitating the relationship between apathy and executive dysfunction in those with CAD. As apathy is a strong predictor of conversion from cognitively normal to mild cognitive impairment, understanding mediators may suggest treatment targets.