Probing the Biological Underpinnings of Advanced Brain Ageing in Schizophrenia

Abstract

BackgroundRecent evidence suggests that patients with schizophrenia may show advanced brain ageing, particularly evident after the first year of onset. However, it is unclear if accelerated ageing relents, persists or continues to increase over time. The underlying causal factors are also poorly understood. Disruptions in glutamate function, oxidative stress, and inflammation may all contribute to progressive brain changes in people with schizophrenia. We examine whether brain ageing differs between early and established stages of schizophrenia, correlates with symptom severity and varies with markers of brain function, oxidative status and inflammatory burden.MethodsTwo brain-age prediction models assessed 112 participants (34 recent onset psychosis, 36 established schizophrenia, 42 healthy controls). Brain age gap (BAG) was calculated by subtracting chronological age from predicted age. Shapley’s additive explanations (SHAP) identified influential structural magnetic resonance imaging (MRI) features driving brain-age prediction. Linear regression models and partial correlations, adjusting for age, explored associations between BAG and neurometabolites, inflammatory markers, medication exposure and clinical scores in the whole sample.ResultsThe established schizophrenia group showed higher BAG (Mean = 6.21, SD = 7.30) compared to healthy individuals (Mean = -0.01, SD = 9.10), while recent-onset patients (Mean = 4.23, SD = 9.25) did not differ significantly from healthy individuals. The top 10 SHAP features diving the BAG included ventricular enlargement and total grey matter volume, which was similar in psychosis to healthy individuals. In a combined psychosis group (established + recent-onset), higher BAG correlated with more severe symptoms (PANSS total, general, and anxiodepressive subscales). BAG positively associated with Magnetic Resonance Spectroscopy measured glutathione and negatively with N-Acetyl Aspartate.DiscussionAccelerated brain age in schizophrenia may be related to illness severity and poor defence against oxidative stress. The lack of differences in SHAP features between schizophrenia and healthy individuals suggests that the pattern of brain ageing is in keeping with advanced normal ageing. Findings suggest potential treatment targets to improve brain health in schizophrenia, warranting further research.