Accelerated ageing unfolds along the sensorimotor-association cortical axis in schizophrenia: multi-site study

Schizophrenia is associated with a reduced average lifespan due to accelerated ageing. Early studies have predominantly focused on the global brain age gap, limiting our understanding of region-specific ageing. Moreover, the relationship between accelerated ageing and schizophrenia disease progression has not been directly examined.

Our aim was to investigate the cortical spatiotemporal patterns in ageing and disease progression in schizophrenia.

Using multi-site, resting-state functional magnetic resonance imaging data, we analysed intrinsic activity fluctuations in 2353 healthy controls and 546 subjects with schizophrenia. We assessed normative models of ageing trajectories in brain activities in healthy controls, and examined the developmental trajectory of deviations from normative reference ranges with disease progression in schizophrenia.

The ageing trajectories of both groups demonstrated spatiotemporal variability unfolding along the sensorimotor-association cortical axis, characterised by a rapid decline in transmodal association cortices at younger ages and followed by an accelerated decline in primary cortices at older ages. However, schizophrenia exhibited a more rapid rate of decline across the entire cerebral cortex, particularly during the short-duration stage. Further analysis revealed that the spatial variability of disease-induced ageing deviations persisted along the sensorimotor-association cortical axis throughout disease progression. The premature involvement of neurotransmitter systems, including dopamine and serotonin, may underlie accelerated ageing.

Our work uncovers regional ageing trajectories organised along the sensorimotor-association cortical axis, and provides new insights into the mechanisms of atypical ageing and disease progression in schizophrenia.