Multifaceted Brain Age Measures Reveal Premature Brain Aging and Associations with Clinical Manifestations in Schizophrenia

Schizophrenia is a mental disorder with extensive alterations of cerebral gray matter (GM) and white matter (WM) and is known to have advanced brain aging. However, how the structural alterations contribute to brain aging and how brain aging is related to clinical manifestations remain unclear. Here, we estimated the bias-free multifaceted brain age measures in patients with schizophrenia (N=147) using structural and diffusion magnetic resonance imaging data. We calculated feature importance to estimate regional contributions to advanced brain aging in schizophrenia. Furthermore, regression analyses were conducted to test the associations of brain age with illness duration, onset age, symptom severity, and intelligence quotient. The patients with schizophrenia manifested significantly old-appearing brain age (P<.001) in both GM and WM compared with the healthy norm. The GM and WM structures contributing to the advanced brain aging were mostly located in the frontal and temporal lobes. Among the features, the GM volume and mean diffusivity of WM were most sensitive to the neuropathological changes in schizophrenia. The WM brain age index was associated with a negative symptom score (P=.006), and the WM and multimodal brain age indices demonstrated negative associations with the intelligence quotient (P=.037; P=.040, respectively). Moreover, brain age exhibited associations with the onset age (P=.006) but no associations with the illness duration, which may support the early-hit non-progression hypothesis. In conclusion, our study reveals the structural underpinnings of premature brain aging in schizophrenia and its clinical significance. The brain age measures might be a potentially informative biomarker for stratification and prognostication of patients with schizophrenia.